RIP1 inhibitory compounds and methods for making and using the same

ABSTRACT

Disclosed herein are kinase inhibitory compounds, such as a receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, as well as pharmaceutical compositions and combinations comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions, and/or combinations may be used to treat or prevent a kinase-associated disease or condition, particularly a RIP1-associated disease or condition.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing date of U.S.Provisional Patent Application Nos. 62/897,223, filed on Sep. 6, 2019;62/932,404, filed on Nov. 7, 2019, 63/001,016, filed on Mar. 27, 2020,U.S. 63/004,290, filed on Apr. 2, 2020 and 63/004,319, filed on Apr. 2,2020.

FIELD

The present disclosure concerns compounds and methods of making andusing the compounds, such as for inhibiting receptor-interactingprotein-1 kinase (“RIP1”), and for treating diseases and/or conditionsrelated to RIP1.

BACKGROUND

Receptor-interacting protein-1 kinase (referred to herein as “RIP1”)belongs to the tyrosine kinase-like family and is a serine/threonineprotein kinase involved in innate immune signaling. RIP1 plays a centralrole in regulating cell signaling and its role in programmed cell deathhas been linked to various inflammatory diseases, such as inflammatorybowel disease, psoriasis, and other diseases and/or conditionsassociated with inflammation and/or necroptotic cell death.

SUMMARY

Disclosed compounds according to the present disclosure have a

a Formula I

wherein X is C or N;

Y is selected from O, S and CH₂;

the ring system denoted by

is a bicyclic heteroaryl optionally substituted on ring A, ring B, orboth by one or more R⁴ groups;

L is a divalent moiety selected from W, a heteroatom; C₁₋₄alkyl, orC₃₋₆cycloalkyl;

Z is C₁₋₁₀aliphatic Z is C₁₋₁₀aliphatic, including cycloaliphatic,heteroaromatic or aromatic;

each R¹ independently is a halogen, —C═CH, or a -linker-R⁶ group,wherein the linker is a bond or R^(a) provided that R^(a) is not H or D,and R⁶ is heterocyclyl, R^(b), —C(R^(f))₃, or —C(R^(f))═C(R^(f))₂;

R² is R^(a);

each R⁴ independently is oxo, C₃₋₆heterocyclyl or R^(e);

-   -   R^(a) is independently for each occurrence H or D, except for        embodiments where L is R^(a), C₁₋₁₀haloaliphatic, C₁₋₁₀aromatic,        C₃₋₆ heterocyclic, or C₃₋₁₀spiroheterocyclic;    -   R^(b) is independently for each occurrence —OH, —SH, —OR^(c),        —SR^(c), —NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c),        —C(O)NR^(d)R^(d), —OC(O)NR^(d)R^(d), —OC(O)C₁₋₁₀alkyl        substituted with one or two NR^(d)R^(d), carboxyl, or a        combination thereof, and optionally further substituted with an        aromatic moiety, —SH, —O-acyl, or —C(O)NH₂;    -   R^(c) is independently for each occurrence C₁₋₁₀alkyl, which can        be substituted with 1, 2 or 3 R^(e), C₂₋₁₀alkenyl, which can be        substituted with 1, 2 or 3 R^(e), C₂₋₁₀alkynyl, which can be        substituted with 1, 2 or 3 R^(e), C₃₋₆cycloalkyl, which can be        substituted with 1, 2 or 3 R^(e), or C₅₋₁₀aromatic, which can be        substituted with 1, 2 or 3 R^(e);    -   R^(d) is independently for each occurrence H; C₁₋₆ alkyl, which        can be substituted with 1, 2 or 3 R^(e) or a C₃₋₉heterocyclyl;        C₃₋₆cycloalkyl, which can be substituted with 1, 2 or 3 R^(e);        C₃₋₆heterocyclic, which can be substituted with 1, 2 or 3 R^(e);        C₅₋₁₀aryl, which can be substituted with 1, 2 or 3 R^(b);        C₅₋₁₀heteroaryl, which can be substituted with 1, 2 or 3 R^(e);        or two R^(d) groups together with the nitrogen bound thereto        provide a C₃₋₉heterocyclic, which can be substituted with one or        more R^(e)), or a C₅₋₁₀heteroaryl, which can be substituted with        one or more R^(e);    -   R^(e) is independently for each occurrence halogen, C₁₋₆alkyl,        C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₅₋₁₀heteroaryl, or —OR^(a); and    -   R^(f) is independently for each occurrence -alkyl-phosphate,        R^(a), R^(b), or R^(e), or two R^(f) groups together with the        carbon atom bound thereto provide a C₂₋₆alkenyl group, a        C₃₋₆cycloalkyl group, which can be substituted with one or more        R^(e), or a C₃₋₁₀heterocyclic, which can be substituted with one        or more R^(e) or acyl;

m is 1, 2, 3, or 4; and

n is 0, 1 or 2.

Disclosed embodiments also include pharmaceutical compositionscomprising disclosed compounds. Such compositions may further comprisean excipient, an additional therapeutic agent, or combinations thereof.

A method may comprise administering to a subject a disclosed compound orcompounds, or a composition comprising a disclosed compounds orcompounds. A particular embodiment concerns contacting areceptor-interacting protein-1 (RIP1) kinase with a disclosed compoundor compounds, or a composition comprising a disclosed compounds orcompounds. The method may be an in vitro method or an in vivo method,such as when the RIP1 kinase is in a subject.

In some embodiments, the method may comprise administering one or moreof the disclosed compounds, or a composition thereof, to a subject. Themethod may be a method for treating a disease in a subject and/or maycomprise administering to the subject (i) a therapeutically effectiveamount of a disclosed compound or a stereoisomer, an N-oxide, atautomer, or a prodrug thereof; or (ii) a therapeutically effectiveamount of a pharmaceutical composition of the compound. In someembodiments, the subject may have, or may be suspected of having ordeveloping, the disease, such as a disease involving areceptor-interacting protein-1 (RIP1) kinase. Examples of diseases thatcan be treated according to this method embodiment include diseases ordisorders associated with inflammation, necroptosis, or both. In certainembodiments, diseases to be treated with the present compounds areinflammatory or immune-regulatory disorders, including autoimmune andproliferative disorders. Exemplary diseases are disclosed herein.

The foregoing and other objects and features of the present disclosurewill become more apparent from the following detailed description.

DETAILED DESCRIPTION I. Overview of Terms

The following explanations of terms and methods are provided to betterdescribe the present disclosure and to guide those of ordinary skill inthe art in the practice of the present disclosure. The singular forms“a,” “an,” and “the” refer to one or more than one, unless the contextclearly dictates otherwise. The term “or” refers to a single element ofstated alternative elements or a combination of two or more elements,unless the context clearly indicates otherwise. As used herein,“comprises” means “includes.” Thus, “comprising A or B,” means“including A, B, or A and B,” without excluding additional elements. Allreferences, including patents and patent applications cited herein, areincorporated by reference.

Unless otherwise indicated, all numbers expressing quantities ofcomponents, molecular weights, percentages, temperatures, times, and soforth, as used in the specification or claims are to be understood asbeing modified by the term “about.” Accordingly, unless otherwiseindicated, implicitly or explicitly, the numerical parameters set forthare approximations that may depend on the desired properties soughtand/or limits of detection under standard test conditions/methods. Whendirectly and explicitly distinguishing embodiments from discussed priorart, the embodiment numbers are not approximates unless the word “about”is expressly recited.

Unless explained otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood to one of ordinaryskill in the art to which this disclosure pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, suitable methods andmaterials are described below. The materials, methods, and examples areillustrative only and not intended to be limiting.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to include hydrogen so thateach carbon conforms to a valence of four. For example, in the structureon the left-hand side of the schematic below there are nine hydrogenatoms implied. The nine hydrogen atoms are depicted in the right-handstructure.

Sometimes a particular atom in a structure is described in textualformula as having a hydrogen or hydrogen atoms, for example —CH₂CH₂—. Itwill be understood by a person of ordinary skill in the art that theaforementioned descriptive techniques are common in the chemical arts toprovide brevity and simplicity to description of organic structures.

If an R group is depicted as “floating” on a ring system, as for examplewith R′ in the group:

then, unless otherwise defined, a substituent R (e.g., R¹ above) canreside on any atom of the fused bicyclic ring system, excluding the atomcarrying the bond with the “

” symbol, so long as a stable structure is formed.

When a group R is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

where, in this example, y can be more than one, assuming each replaces acurrently depicted, implied, or expressly defined hydrogen on the ring;then, unless otherwise defined, two R's can reside on the same carbon. Asimple example is when R is a methyl group. The depicted structure canexist as a geminal dimethyl on a carbon of the depicted ring (an“annular” carbon). In another example, two R's on the same carbon,including that same carbon, can be included in a ring, thus creating aspirocyclic ring (a “spirocyclyl” group) structure.

As used herein, the term “substituted” refers to all subsequentmodifiers in a term, for example in the term “substitutedarylC₁₋₈alkyl,” substitution may occur on the “C₁₋₈alkyl” portion, the“aryl” portion or both portions of the arylC₁₋₈alkyl group.

“Substituted,” when used to modify a specified group or moiety, meansthat at least one, and perhaps two or more, hydrogen atoms of thespecified group or moiety is independently replaced with the same ordifferent substituent groups as defined below. In a particularembodiment, a group, moiety or substituent may be substituted orunsubstituted, unless expressly defined as either “unsubstituted” or“substituted.” Accordingly, any of the groups specified herein may beunsubstituted or substituted unless the context indicates otherwise or aparticular structural formula precludes substitution. In particularembodiments, a substituent may or may not be expressly defined assubstituted, but is still contemplated to be optionally substituted. Forexample, an “aliphatic” or a “cyclic” moiety may be unsubstituted orsubstituted, but an “unsubstituted aliphatic” or an “unsubstitutedcyclic” is not substituted.

“Substituents” or “substituent groups” for substituting for one or morehydrogen atoms on saturated carbon atoms in the specified group ormoiety can be, unless otherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰,—N(R⁸⁰)₂, haloalkyl, perhaloalkyl, —CN, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰, —SO₃⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —P(O)(O⁻)₂(M⁺)₂,—P(O)(O⁻)₂M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰,—C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)N(R⁸⁰)₂, —C(NR⁷⁰)(R⁸⁰)₂,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC (S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰,—NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰ isC₁₋₁₀aliphatic, heteroaliphatic, or cycloaliphatic, typically,C₁₋₆aliphatic, more typically C₁₋₆alkyl, where R⁶⁰ optionally may besubstituted; each R⁷⁰ is independently for each occurrence hydrogen orR⁶⁰; each R⁸⁰ is independently for each occurrence R⁷⁰ or alternatively,two R⁸⁰ groups, taken together with the nitrogen atom to which they arebonded, form a 3- to 7-membered heterocycloaliphatic, which optionallyincludes from 1 to 4 of the same or different additional heteroatomsselected from O, N and S, of which N optionally has R⁷⁰ substitution,such as H or C₁-C₃alkyl substitution; and each M⁺ is a counter ion witha net single positive charge. Each M⁺ is independently for eachoccurrence, for example, an alkali metal ion, such as K⁺, Na⁺, Li⁺; anammonium ion, such as ⁺N(R⁶⁰)₄; a protonated amino acid ion, such as alysine ion, or an arginine ion; or an alkaline metal earth ion, such as[Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5) (a subscript “0.5” means,for example, that one of the counter ions for such divalent alkali earthions can be an ionized form of a compound of the disclosure and theother a typical counter ion such as chloride, or two ionized compoundscan serve as counter ions for such divalent alkali earth ions, or adoubly ionized compound can serve as the counter ion for such divalentalkali earth ions). As specific examples, —N(R⁸⁰)₂ includes —NH₂,—NH-alkyl, —NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl,4N-methyl-piperazin-1-yl, N-morpholinyl and the like. Any two hydrogenatoms on a single carbon also can be replaced with, for example, ═O,═NR⁷⁰, ═N—OR⁷⁰, ═N₂ or ═S.

Substituent groups for replacing hydrogen atoms on unsaturated carbonatoms in groups containing unsaturated carbons are, unless otherwisespecified, —R⁶⁰, halo, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —N(R⁸⁰)₂, perhaloalkyl, —CN,—OCN, —SCN, —NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃R⁷⁰, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃⁻M⁺, —OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —PO₃ ⁻²M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂,—C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰,—C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)N(R⁸⁰)₂, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺,—OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺,—NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰N(R⁸⁰)₂, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previouslydefined. In an independent embodiment, the substituents are not —O⁻M⁺,—OR⁷⁰, —SR⁷⁰, or —S⁻M⁺.

Substituent groups for replacing hydrogen atoms on nitrogen atoms ingroups containing such nitrogen atoms are, unless otherwise specified,—R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —N(R⁸⁰)₂, perhaloalkyl, —CN, —NO,—NO₂, —S(O)₂R⁷⁰, —SO₃M⁺, —SO₃R⁷⁰, —OS(O)₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —PO₃²⁻(M⁺)₂, —PO₃ ²⁻M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰,—C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂R⁷⁰, —OC(S)R⁷⁰,—NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰,R⁷⁰, R⁸⁰ and M⁺ are as previously defined.

In one embodiment, a group that is substituted has at least onesubstituent up to the number of substituents possible for a particularmoiety, such as 1 substituent, 2 substituents, 3 substituents, or 4substituents.

Additionally, in embodiments where a group or moiety is substituted witha substituted substituent, the nesting of such substituted substituentsis limited to three, thereby preventing the formation of polymers. Thus,in a group or moiety comprising a first group that is a substituent on asecond group that is itself a substituent on a third group, which isattached to the parent structure, the first (outermost) group can onlybe substituted with unsubstituted substituents. For example, in a groupcomprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substitutedwith substituents that are not themselves substituted.

Any group or moiety defined herein can be connected to any other portionof a disclosed structure, such as a parent or core structure, as wouldbe understood by a person of ordinary skill in the art, such as byconsidering valence rules, comparison to exemplary species, and/orconsidering functionality, unless the connectivity of the group ormoiety to the other portion of the structure is expressly stated, or isimplied by context.

“Acyl” refers to the group —C(O)R, where R is H, aliphatic,heteroaliphatic, or aromatic (including both aryl and heteroaryl).Exemplary acyl moieties include, but are not limited to, —C(O)H,—C(O)alkyl, —C(O)C₁-C₆alkyl, —C(O)C₁-C₆haloalkyl, —C(O)cycloalkyl,—C(O)alkenyl, —C(O)cycloalkenyl, —C(O)aryl, —C(O)heteroaryl, or—C(O)heterocyclyl. Specific examples include, —C(O)H, —C(O)Me, —C(O)Et,or —C(O)cyclopropyl.

“Aliphatic” refers to a substantially hydrocarbon-based group or moiety.An aliphatic group or moiety can be acyclic, including alkyl, alkenyl,or alkynyl groups (as well as alkylene, alkenylene, or alkynylenegroups), cyclic versions thereof, such as cycloaliphatic groups ormoieties including cycloalkyl, cycloalkenyl or cycloalkynyl, and furtherincluding straight- and branched-chain arrangements, and all stereo andposition isomers as well. Unless expressly stated otherwise, analiphatic group contains from one to twenty-five carbon atoms (C₁₋₂₅);for example, from one to fifteen (C₁₋₁₅), from one to ten (C₁₋₁₀) fromone to six (C₁₋₆), or from one to four carbon atoms (C₁₋₄) for anacyclic aliphatic group or moiety, or from three to fifteen (C₃₋₁₅) fromthree to ten (C₃₋₁₀), from three to six (C₃₋₆), or from three to four(C₃₋₄) carbon atoms for a cycloaliphatic group or moiety. An aliphaticgroup may be substituted or unsubstituted, unless expressly referred toas an “unsubstituted aliphatic” or a “substituted aliphatic.” Analiphatic group can be substituted with one or more substituents (up totwo substituents for each methylene carbon in an aliphatic chain, or upto one substituent for each carbon of a —C═C— double bond in analiphatic chain, or up to one substituent for a carbon of a terminalmethine group).

“Lower aliphatic” refers to an aliphatic group containing from one toten carbon atoms (C₁₋₁₀), such as from one to six (C₁₋₆), or from one tofour (C₁₋₄) carbon atoms; or from three to ten (C₃₋₁₀), such as fromthree to six (C₃₋₆) carbon atoms for a lower cycloaliphatic group.

“Alkoxy” refers to the group OR, where R is a substituted orunsubstituted alkyl or a substituted or unsubstituted cycloalkyl group.In certain examples R is a C₁₋₆alkyl group or a C₃₋₆ cycloalkyl group.Methoxy (—OCH₃) and ethoxy (—OCH₂CH₃) are exemplary alkoxy groups. In asubstituted alkoxy, R is substituted alkyl or substituted cycloalkyl,examples of which in the presently disclosed compounds includehaloalkoxy groups, such as —OCF₂H.

“Alkoxyalkyl” refers to the group -alkyl-OR, where R is a substituted orunsubstituted alkyl or a substituted or unsubstituted cycloalkyl group;—CH₂CH₂—O—CH₂CH₃ is an exemplary alkoxyalkyl group.

“Alkyl” refers to a saturated aliphatic hydrocarbyl group having from 1to at least 25 (C₁₋₂₅) carbon atoms, more typically 1 to 10 (C₁₋₁₀)carbon atoms such as 1 to 6 (C₁₋₆) carbon atoms. An alkyl moiety may besubstituted or unsubstituted. This term includes, by way of example,linear and branched hydrocarbyl groups such as methyl (CH₃), ethyl(—CH₂CH₃), n-propyl (—CH₂CH₂CH₃), isopropyl (—CH(CH₃)₂), n-butyl(—CH₂CH₂CH₂CH₃), isobutyl (—CH₂CH₂(CH₃)₂), sec-butyl (—CH(CH₃)(CH₂CH₃),t-butyl (—C(CH₃)₃), n-pentyl (—CH₂CH₂CH₂CH₂CH₃), and neopentyl(—CH₂C(CH₃)₃).

“Amino” refers to the group —NH₂, —NHR, or —NRR, where each Rindependently is selected from H, aliphatic, heteroaliphatic, aromatic,including both aryl and heteroaryl, or heterocycloaliphatic, or two Rgroups together with the nitrogen attached thereto form a heterocyclicring. Examples of such heterocyclic rings include those wherein two Rgroups together with the nitrogen to which they are attached form a—(CH₂)₂₋₅ ring optionally interrupted by one or two heteroatom groups,such as —O— or —N(R^(g)) such as in the groups

wherein R^(g) is R⁷⁰, —C(O)R⁷⁰, —C(O)OR⁶⁰ or —C(O)N(R⁸⁰)₂.

“Amide” refers to the group —N(R)acyl, wherein R is hydrogen,heteroaliphatic, or aliphatic, such as alkyl, particularly C₁₋₆ alkyl.

“Aromatic” refers to a cyclic, conjugated group or moiety of, unlessspecified otherwise, from 5 to 15 ring atoms having a single ring (e.g.,phenyl, pyridinyl, or pyrazolyl) or multiple condensed rings in which atleast one ring is aromatic (e.g., naphthyl, indolyl, orpyrazolopyridinyl), that is at least one ring, and optionally multiplecondensed rings, have a continuous, delocalized π-electron system.Typically, the number of out of plane π-electrons corresponds to theHückel rule (4n+2). The point of attachment to the parent structuretypically is through an aromatic portion of the condensed ring system.For example,

However, in certain examples, context or express disclosure may indicatethat the point of attachment is through a non-aromatic portion of thecondensed ring system. For example,

An aromatic group or moiety may comprise only carbon atoms in the ring,such as in an aryl group or moiety, or it may comprise one or more ringcarbon atoms and one or more ring heteroatoms comprising a lone pair ofelectrons (e.g. S, O, N, P, or Si), such as in a heteroaryl group ormoiety. Unless otherwise stated, an aromatic group may be substituted orunsubstituted.

“Aryl” refers to an aromatic carbocyclic group of, unless specifiedotherwise, from 6 to 15 carbon atoms having a single ring (e.g., phenyl)or multiple condensed rings in which at least one ring is aromatic(e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, and the like). If anyaromatic ring portion contains a heteroatom, the group is heteroaryl andnot aryl. Aryl groups may be, for example, monocyclic, bicyclic,tricyclic or tetracyclic. Unless otherwise stated, an aryl group may besubstituted or unsubstituted.

“Araliphatic” refers to an aryl group attached to the parent via analiphatic moiety. Araliphatic includes aralkyl or arylalkyl groups suchas benzyl and phenylethyl.

“Carboxyl” refers to —CO₂H.

“Carboxamide” refers to —C(O)amino.

“Carboxyl ester” or “carboxy ester” refers to the group —C(O)OR, where Ris aliphatic, heteroaliphatic, or aromatic (including both aryl andheteroaryl).

“Carboxylate” refers to —C(O)O⁻ or salts thereof.

“Cyano” refers to the group —CN.

“Cycloaliphatic” refers to a cyclic aliphatic group having a single ring(e.g., cyclohexyl), or multiple rings, such as in a fused, bridged orspirocyclic system, the ring or at least one of the rings in the systemis aliphatic. Typically, the point of attachment to the parent structureis through an aliphatic portion of the multiple ring system.Cycloaliphatic includes saturated and unsaturated systems, includingcycloalkyl, cycloalkenyl and cycloalkynyl. A cycloaliphatic group maycontain from three to twenty-five carbon atoms; for example, from threeto fifteen, from three to ten, or from three to six carbon atoms. Unlessotherwise stated, a cycloaliphatic group may be substituted orunsubstituted. Exemplary cycloaliphatic groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, or cyclohexenyl.

“Halo,” “halide” or “halogen” refers to fluoro, chloro, bromo or iodo.

“Haloalkyl” refers to an alkyl moiety substituted with one or morehalogens. Exemplary haloalkyl moieties include —CH₂F, —CHF₂ and —CF₃.

“Heteroaliphatic” refers to an aliphatic compound or group having atleast one heteroatom and at least one carbon atom, i.e., at least onecarbon atom from an aliphatic compound or group comprising at least twocarbon atoms, has been replaced with an atom having at least one lonepair of electrons, typically nitrogen, oxygen, phosphorus, silicon, orsulfur. Heteroaliphatic compounds or groups may be substituted orunsubstituted, branched or unbranched, chiral or achiral, and/or acyclicor cyclic, such as a heterocycloaliphatic group.

“Heteroaryl” refers to an aromatic group or moiety having, unlessspecified otherwise, from 5 to 15 ring atoms comprising at least onecarbon atom and at least one heteroatom, such as N, S, O, P, or Si. Aheteroaryl group or moiety may comprise a single ring (e.g., pyridinyl,pyrimidinyl or pyrazolyl) or multiple condensed rings (e.g., indolyl,benzopyrazolyl, or pyrazolopyridinyl). Heteroaryl groups or moiety maybe, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unlessotherwise stated, a heteroaryl group or moiety may be substituted orunsubstituted.

“Heterocyclyl,” “heterocyclo” and “heterocycle” refer to both aromaticand non-aromatic ring systems, and more specifically refer to a stablethree- to fifteen-membered ring moiety comprising at least one carbonatom, and typically plural carbon atoms, and at least one, such as fromone to five, heteroatoms. The heteroatom(s) may be nitrogen, phosphorus,oxygen, silicon or sulfur atom(s). The heterocyclyl moiety may be amonocyclic moiety, or may comprise multiple rings, such as in a bicyclicor tricyclic ring system, provided that at least one of the ringscontains a heteroatom. Such a multiple ring moiety can include fused orbridged ring systems as well as spirocyclic systems; and any nitrogen,phosphorus, carbon, silicon or sulfur atoms in the heterocyclyl moietycan be optionally oxidized to various oxidation states. For convenience,nitrogens, particularly, but not exclusively, those defined as annulararomatic nitrogens, are meant to include their corresponding N-oxideform, although not explicitly defined as such in a particular example.Thus, for a compound having, for example, a pyridinyl ring, thecorresponding pyridinyl-N-oxide is included as another compound of thedisclosure, unless expressly excluded or excluded by context. Inaddition, annular nitrogen atoms can be optionally quaternized.Heterocycle includes heteroaryl moieties, and heteroalicyclyl orheterocycloaliphatic moieties, which are heterocyclyl rings that arepartially or fully saturated. Examples of heterocyclyl groups include,but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane,diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,dioxaphospholanyl, and oxadiazolyl.

“Hydroxyl” refers to the group —OH.

“Nitro” refers to the group —NO₂.

“Phosphate” refers to the group —O—P(O)(OR′)₂, where each —OR′independently is —OH; —O-aliphatic, such as —O-alkyl or —O-cycloalkyl;—O-aromatic, including both —O-aryl and —O-heteroaryl; —O-aralkyl; or—OR′ is —O-M⁺, where M⁺ is a counter ion with a single positive charge.Each M⁺ may be an alkali ion, such as K⁺, Na⁺, Li⁺; an ammonium ion,such as ⁺N(R″)₄ where R″ is H, aliphatic, heteroaliphatic, or aromatic(including both aryl and heteroaryl); or an alkaline earth ion, such as[Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5). Phosphonooxyalkyl refers tothe group alkyl-phosphate, such as, for example, —CH₂OP(O)(OH)₂, or asalt thereof, such as —CH₂OP(O)(O⁻Na⁺)₂, and(((dialkoxyphosphoryl)oxy)alkyl) refers to the dialkyl ester of aphosphonooxyalkyl group, such as, for example, —CH₂OP(O)(O-tert-butyl)₂.

“Phosphonate” refers to the group —P(O)(OR′)₂, where each —OR′independently is —OH; —O-aliphatic such as —O-alkyl or —O-cycloalkyl;—O-aromatic, including both —O-aryl and —O-heteroaryl; or —O-aralkyl; or—OR′ is —O-M⁺, and M⁺ is a counter ion with a single positive charge.Each M⁺ is a positively charged counterion and may be, by way ofexample, an alkali metal ion, such as K⁺, Na⁺, Li⁺; an ammonium ion,such as ⁺N(R″)₄ where R″ is H, aliphatic, heteroaliphatic, or aromatic(including both aryl and heteroaryl); or an alkaline earth metal ion,such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5). Phosphonoalkylrefers to the group alkyl-phosphonate, such as, for example,—CH₂P(O)(OH)₂, or —CH₂P(O)(O⁻Na⁺)₂, and ((dialkoxyphosphoryl)alkyl)refers to the dialkyl ester of a phosphonoalkyl group, such as, forexample, —CH₂P(O)(O-tert-butyl)₂.

“Patient” or “Subject” may refer generally to any living being, but moretypically refers to mammals and other animals, particularly humans. Thusdisclosed methods are applicable to both human therapy and veterinaryapplications.

“Pharmaceutically acceptable excipient” refers to a substance, otherthan the active ingredient, that is included in a composition comprisingthe active ingredient. As used herein, an excipient may be incorporatedwithin particles of a pharmaceutical composition, or it may bephysically mixed with particles of a pharmaceutical composition. Anexcipient can be used, for example, to dilute an active agent and/or tomodify properties of a pharmaceutical composition. Excipients caninclude, but are not limited to, anti-adherents, binders, coatings,enteric coatings, disintegrants, flavorings, sweeteners, colorants,lubricants, glidants, sorbents, preservatives, carriers or vehicles.Excipients may be starches and modified starches, cellulose andcellulose derivatives, saccharides and their derivatives such asdisaccharides, polysaccharides and sugar alcohols, protein, syntheticpolymers, crosslinked polymers, antioxidants, amino acids orpreservatives. Exemplary excipients include, but are not limited to,magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose,starches, hydroxypropyl cellulose, hydroxypropyl methylcellulose,xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP),polyethyleneglycol (PEG), tocopheryl polyethylene glycol 1000 succinate(also known as vitamin E TPGS, or TPGS), carboxy methyl cellulose,dipalmitoyl phosphatidyl choline (DPPC), vitamin A, vitamin E, vitaminC, retinyl palmitate, selenium, cysteine, methionine, citric acid,sodium citrate, methyl paraben, propyl paraben, sugar, silica, talc,magnesium carbonate, sodium starch glycolate, tartrazine, aspartame,benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulphiteor lanolin.

An “adjuvant” is a component that modifies the effect of other agents,typically the active ingredient. Adjuvants are often pharmacologicaland/or immunological agents. An adjuvant may modify the effect of anactive ingredient by increasing an immune response. An adjuvant may alsoact as a stabilizing agent for a formulation. Exemplary adjuvantsinclude, but are not limited to, aluminum hydroxide, alum, aluminumphosphate, killed bacteria, squalene, detergents, cytokines, paraffinoil, and combination adjuvants, such as Freund's complete adjuvant orFreund's incomplete adjuvant.

“Pharmaceutically acceptable carrier” refers to an excipient that is acarrier or vehicle, such as a suspension aid, solubilizing aid, oraerosolization aid. Remington. The Science and Practice of Pharmacy, TheUniversity of the Sciences in Philadelphia, Editor, Lippincott,Williams, & Wilkins, Philadelphia, Pa., 21^(st) Edition (2005),incorporated herein by reference, describes exemplary compositions andformulations suitable for pharmaceutical delivery of one or moretherapeutic compositions and additional pharmaceutical agents.

In general, the nature of the carrier will depend on the particular modeof administration being employed. For instance, parenteral formulationsusually comprise injectable fluids that include pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. In some examples, the pharmaceutically acceptable carrier maybe sterile to be suitable for administration to a subject (for example,by parenteral, intramuscular, or subcutaneous injection). In addition tobiologically-neutral carriers, pharmaceutical compositions to beadministered can contain minor amounts of non-toxic auxiliarysubstances, such as wetting or emulsifying agents, preservatives, and pHbuffering agents and the like, for example sodium acetate or sorbitanmonolaurate.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound that are derived from a variety of organic andinorganic counter ions as will be known to a person of ordinary skill inthe art and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate, and the like. “Pharmaceutically acceptable acidaddition salts” are a subset of “pharmaceutically acceptable salts” thatretain the biological effectiveness of the free bases while formed byacid partners. In particular, the disclosed compounds form salts with avariety of pharmaceutically acceptable acids, including, withoutlimitation, inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like, as well asorganic acids such as amino acids, formic acid, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,benzene sulfonic acid, isethionic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoicacid and the like. “Pharmaceutically acceptable base addition salts” area subset of “pharmaceutically acceptable salts” that are derived frominorganic bases such as sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Exemplary salts are the ammonium, potassium, sodium, calcium, andmagnesium salts. Salts derived from pharmaceutically acceptable organicbases include, but are not limited to, salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, methylglucamine, theobromine,purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine,dicyclohexylamine, choline, and caffeine. (See, for example, S. M.Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19which is incorporated herein by reference.) In particular disclosedembodiments, the compounds may be a formate, trifluoroactate,hydrochloride or sodium salt.

“Effective amount” with respect to a compound or pharmaceuticalcomposition refers to an amount of the compound or pharmaceuticalcomposition sufficient to achieve a particular desired result, such asto inhibit a protein or enzyme. In particular embodiments, an “effectiveamount” is an amount sufficient to inhibit RIP1; to elicit a desiredbiological or medical response in a tissue, system, subject or patient;to treat a specified disorder or disease; to ameliorate or eradicate oneor more of its symptoms; and/or to prevent the occurrence of the diseaseor disorder. The amount of a compound which constitutes an “effectiveamount” may vary depending on the compound, the desired result, thedisease state and its severity, the size, age, and gender of the patientto be treated and the like, as will be understood by a person ofordinary skill in the art.

“Prodrug” refers to compounds that are transformed in vivo to yield abiologically active compound, or a compound more biologically activethan the parent compound. In vivo transformation may occur, for example,by hydrolysis or enzymatic conversion. Common examples of prodrugmoieties include, but are not limited to, ester and amide forms of acompound having an active form bearing a carboxylic acid moiety.Examples of pharmaceutically acceptable esters of the compounds of thisdisclosure include, but are not limited to, esters of phosphate groupsand carboxylic acids, such as aliphatic esters, particularly alkylesters (for example C₁₋₆alkyl esters). Other prodrug moieties includephosphate esters, such as —CH₂O—P(O)(OR′)₂ or a salt thereof, wherein R′is H or C₁₋₆ alkyl. Acceptable esters also include cycloalkyl esters andarylalkyl esters such as, but not limited to benzyl. Examples ofpharmaceutically acceptable amides of the compounds of this disclosureinclude, but are not limited to, primary amides, and secondary andtertiary alkyl amides (for example with between about one and about sixcarbons). Amides and esters of disclosed exemplary embodiments ofcompounds according to the present disclosure can be prepared accordingto conventional methods. A thorough discussion of prodrugs is providedin T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of a solute. The solvent can be an organicsolvent, an inorganic solvent, or a mixture of both. Exemplary solventsinclude, but are not limited to, alcohols, such as methanol, ethanol,propanol; amides such as N,N-dialiphatic amides, such asN,N-dimethylformamide; tetrahydrofuran; alkylsulfoxides, such asdimethylsulfoxide; water; and combinations thereof. The compoundsdescribed herein can exist in un-solvated as well as solvated forms whencombined with solvents, pharmaceutically acceptable or not, such aswater, ethanol, and the like. Solvated forms of the presently disclosedcompounds are within the scope of the embodiments disclosed herein.

“Sulfonamide” refers to the group or moiety —SO₂amino, or —N(R)sulfonyl,where R is H, aliphatic, heteroaliphatic, or aromatic (including botharyl and heteroaryl).

“Sulfanyl” refers to the group or —SH, —S-aliphatic, —S-heteroaliphatic,—S-aromatic, (including both-S-aryl and —S-heteroaryl).

“Sulfinyl” refers to the group or moiety —S(O)H, —S(O)aliphatic,—S(O)heteroaliphatic, or —S(O)aromatic (including both —S(O)aryl and—S(O)heteroaryl).

“Sulfonyl” refers to the group: —SO₂H, —SO₂aliphatic,—SO₂heteroaliphatic, —SO₂aromatic (including both —SO₂aryl and—SO₂heteroaryl).

“Treating” or “treatment” as used herein concerns treatment of a diseaseor condition of interest in a patient or subject, particularly a humanhaving the disease or condition of interest, and includes by way ofexample, and without limitation:

(i) preventing the disease or condition from occurring in a patient orsubject, in particular, when such patient or subject is predisposed tothe condition but has not yet been diagnosed as having it;

(ii) inhibiting the disease or condition, for example, arresting orslowing its development;

(iii) relieving the disease or condition, for example, causingdiminution of a symptom or regression of the disease or condition or asymptom thereof; or

(iv) stabilizing the disease or condition.

As used herein, the terms “disease” and “condition” can be usedinterchangeably or can be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been determined) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, where a more or lessspecific set of symptoms have been identified by clinicians.

The above definitions and the following general formulas are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluoro groups). Such impermissible substitutionpatterns are easily recognized by a person having ordinary skill in theart.

A person of ordinary skill in the art will appreciate that compounds mayexhibit the phenomena of tautomerism, conformational isomerism,geometric isomerism, and/or optical isomerism. For example, certaindisclosed compounds can include one or more chiral centers and/or doublebonds and as a consequence can exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers,diasteromers, and mixtures thereof, such as racemic mixtures. As anotherexample, certain disclosed compounds can exist in several tautomericforms, including the enol form, the keto form, and mixtures thereof. Asthe various compound names, formulae and compound drawings within thespecification and claims can represent only one of the possibletautomeric, conformational isomeric, optical isomeric, or geometricisomeric forms, a person of ordinary skill in the art will appreciatethat the disclosed compounds encompass any tautomeric, conformationalisomeric, optical isomeric, and/or geometric isomeric forms of thecompounds described herein, as well as mixtures of these variousdifferent isomeric forms. Mixtures of different isomeric forms,including mixtures of enantiomers and/or stereoisomers, can be separatedto provide each separate enantiomers and/or stereoisomer usingtechniques known to those of ordinary skill in the art, particularlywith the benefit of the present disclosure. In cases of limitedrotation, e.g. around the amide bond or between two directly attachedrings such as pyridinyl rings, biphenyl groups, and the like,atropisomers are also possible and are also specifically included in thecompounds of the disclosure.

In any embodiments, any or all hydrogens present in the compound, or ina particular group or moiety within the compound, may be replaced by adeuterium or a tritium. Thus, a recitation of alkyl includes deuteratedalkyl, where from one to the maximum number of hydrogens present may bereplaced by deuterium. For example, ethyl refers to both C₂H₅ or C₂H₅where from 1 to 5 hydrogens are replaced by deuterium, such as inC₂D_(x)H_(5-x).

II. RIP1-Active Compounds and Pharmaceutical Compositions ComprisingRIP1-Active Compounds

A. Compounds

Disclosed herein are compounds and pharmaceutical compositionscomprising such compounds that are useful for inhibiting RIP1 and/or fortreating diseases and/or conditions associated with RIP1. In someembodiments, the compounds are selective kinase inhibitors. For example,exemplary compounds are able to selectively inhibit RIP1 over RIP2,RIP3, or both RIP2 and RIP3.

In certain embodiments, the compounds have Formula I

wherein X is C or N;

Y is selected from O, S and CH₂;

the ring system denoted by

is a bicyclic heteroaryl optionally substituted on ring A, ring B, orboth by one or more R⁴ groups;

L is a heteroatom; —CH₂—, —CH₂CH₂—, or C₃₋₆cycloalkyl;

Z is C₁₋₁₀aliphatic Z is C₁₋₁₀aliphatic, including cycloaliphatic,heteroaromatic or aromatic;

each R¹ independently is a halogen, —C═CH, or a -linker-R⁶ group,wherein the linker is a bond or R^(a) provided that R^(a) is not H or D,and R⁶ is heterocyclyl, R^(b), —C(R^(f))₃, or —C(R^(f))═C(R^(f))₂;

R² is R^(a);

each R⁴ independently is oxo, C₃₋₆heterocyclyl or R^(e);

-   -   R^(a) is independently for each occurrence H or D, except for        embodiments where L is R^(a), C₁₋₁₀aliphatic,        C₁₋₁₀haloaliphatic, C₅₋₁₀aromatic, C₃₋₆heterocyclic, or        C₃₋₁₀spiroheterocyclic;    -   R^(b) is independently for each occurrence —OH, —SH, —OR^(c),        —SR^(c), —NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c),        —C(O)NR^(d)R^(d), —OC(O)NR^(d)R^(d), —OC(O)C₁₋₁₀alkyl        substituted with one or two NR^(d)R^(d), carboxyl, or a        combination thereof, and optionally further substituted with an        aromatic moiety, —SH, —O-acyl, or —C(O)NH₂;    -   R^(c) is independently for each occurrence C₁₋₁₀alkyl, which can        be substituted with 1, 2 or 3 R^(e), C₂₋₁₀alkenyl, which can be        substituted with 1, 2 or 3 R^(e), C₂₋₁₀alkynyl, which can be        substituted with 1, 2 or 3 R^(e), C₃₋₆cycloalkyl, which can be        substituted with 1, 2 or 3 R^(e), or C₅₋₁₀aromatic, which can be        substituted with 1, 2 or 3 R^(e);    -   R^(d) is independently for each occurrence H; C₁₋₆alkyl, which        can be substituted with 1, 2 or 3 R^(e) or a C₃₋₉heterocyclyl;        C₃₋₆cycloalkyl, which can be substituted with 1, 2 or 3 R^(e);        C₃₋₆heterocyclic, which can be substituted with 1, 2 or 3 R^(e);        C₅₋₁₀aryl, which can be substituted with 1, 2 or 3 R^(b);        C₅₋₁₀heteroaryl, which can be substituted with 1, 2 or 3 R^(e);        or two R^(d) groups together with the nitrogen bound thereto        provide a C₃₋₉heterocyclic, which can be substituted with one or        more R^(e)), or a C₅₋₁₀heteroaryl, which can be substituted with        one or more R^(e);    -   R^(e) is independently for each occurrence halogen, C₁₋₆ alkyl,        C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₅₋₁₀heteroaryl, or —OR^(a); and    -   R^(f) is independently for each occurrence -alkyl-phosphate,        R^(a), R^(b), or R^(c), or two R^(f) groups together with the        carbon atom bound thereto provide a C₂₋₆alkenyl group, a C₃₋₆        cycloalkyl group, which can be substituted with one or more        R^(e), or a C₃₋₁₀heterocyclic, which can be substituted with one        or more R^(e) or acyl;

m is 1, 2, 3, or 4; and

n is 0, 1 or 2.

In some embodiments, of Formula I, X represents CH, such compounds canbe represented with Formula IA:

In alternative compounds according to Formula I, X is N. Examples ofsuch compounds can be represented by Formula IB:

The compound of claim 1 according to the formula

In one embodiment of Formulas I, IA, IB and IC, ring B is 5-membered or6-membered heteroaryl wherein the heteroaryl has one or two ringnitrogen atoms and the remainder of the ring atoms are carbon.

In certain embodiments of Formulas I, IA, IB and IC, the ring systemdenoted by

is represented by the formulas 1(a)-1(e) illustrated below:

wherein p is 0 or 1; and ring A, ring B, or both optionally aresubstituted by one or more R⁴;

wherein p is 0 or 1; and ring B is optionally substituted by one or moreR⁴;

wherein p is 0 or 1;

or

With reference to Formulas I, IA, IB, IC and ID, and in each combinationof Formulas I, IA, IB, IC and ID with the ring systems illustrated inFormulas 1(a)-1(e), Z is C₁₋₁₀aliphatic Z is C₁₋₁₀aliphatic, includingcycloaliphatic, heteroaromatic or aromatic. More particularly in suchcompounds, Z, when cycloaliphatic may be cyclopentyl, cyclohexyl or thelike. In instances when Z is heteroaromatic, Z may be six-memberedheteroaryl, such as pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, orfive-membered heteroaryl, such as a nitrogen containing five memberedheteroaryl, for example, a diazole, triazole, tetrazole, oxazole,isoxazole or thiazole moiety. Each Z moiety may be substituted, such asby one or more halogen, alkyl, C₃₋₆ cycloalkyl or a combination thereof.The Z moiety may be unsubstituted or substituted with one up to thenumber of potential substitution available sites for substitution. Forexample when Z is phenyl, it can be represented by the formula

where each R⁵ independently is R^(e), and q is 0, 1, 2, 3, 4, or 5.Similarly, when Z is pyridyl, it optionally may be substituted with 1, 2or 3 R⁵ groups. In examples of such embodiments, each R⁵ independentlymay be halogen or C₁₋₆alkyl, such as methyl or fluoro. In someembodiments, q is 1 or 2, but in other embodiments, q is 0.

In some embodiments of Formulas I, IA and IC compounds of the presentdisclosure have a structure according to Formula ID

or a pharmaceutically acceptable salt thereof. A person of ordinaryskill in the art will appreciate that compounds within the scope ofFormula ID also include stereoisomers, N-oxides, tautomers, hydrates,solvates, isotopes, and/or prodrugs thereof, unless otherwise specified.With respect to Formula ID, ring B is heteroaryl, such as a 5-memberedor 6-membered heteroaryl, wherein R³ together with the —N—C(O) moiety towhich it is attached and two ring atoms from ring B form a 5- or6-membered heterocyclyl that is fused to ring B. In forming such a ring,R³ may be selected from C₁₋₁₀aliphatic group optionally substituted withone or more R⁴ groups. In one embodiment wherein R³ together with the—N—C(O) moiety to which it is attached and two ring atoms from ring Bform a 5- or 6-membered heterocyclyl, R³ is a C₁₋₃aliphatic groupsubstituted with 1 or more R⁴ groups. In particular examples, R³ is—CH₂— or —(CH₂)₂— wherein one or more hydrogen atoms is replaced withone or more R⁴ groups. In one embodiment, such compounds can haveFormula 1(b). In some embodiments, ring B is a 5-membered or 6-memberedheteroaryl wherein the heteroaryl has one or two ring nitrogen atoms andthe remainder of the ring atoms are carbon, that is, ring B is not atriazole, triazine, or a heteroaryl comprising an oxygen or sulfur ringatom, such as oxazole, thiazole or isoxazole. In certain embodiments,ring B is pyrazolyl, and in other particular embodiments, ring B ispyridinyl.

Each R¹ independently may be halogen, —C═CH, or a -linker-R⁶ group,wherein the linker is a bond or R^(a), provided that R^(a) is not H orD, and R⁶ is heterocyclyl, R^(b), —C(R^(f))₃, or —C(R^(f))═C(R^(f))₂.

R² is R^(a).

If present, each R⁴ independently is R^(e).

L is a heteroatom or R^(a), provided that R^(a) is not H or D.

Z is C₁₋₁₀aliphatic or aromatic.

m is 1, 2, 3, or 4, and n is 0, 1 or 2.

R^(a) is independently for each occurrence H or D, except forembodiments where L is R^(a), C₁₋₁₀aliphatic, C₁₋₁₀haloaliphatic,C₅₋₁₀aromatic, C₃₋₆heterocyclic, or C₃₋₁₀spiroheterocyclic.

R^(b) is independently for each occurrence —OH, —SH, —OR^(c), —SR^(c),—NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c), —C(O)NR^(d)R^(d),—OC(O)NR^(d)R^(d), —OC(O)C₁₋₁₀alkyl substituted with one or twoNR^(d)R^(d), carboxyl, or a combination thereof, and optionally furthersubstituted with an aromatic moiety, —SH, —O-acyl, or —C(O)NH₂.

R^(c) is independently for each occurrence C₁₋₁₀alkyl, which can besubstituted with 1, 2 or 3 R^(e), C₂₋₁₀alkenyl, which can be substitutedwith 1, 2 or 3 R^(e), C₂₋₁₀alkynyl, which can be substituted with 1, 2or 3 R^(e), C₃₋₆ cycloalkyl, which can be substituted with 1, 2 or 3R^(e), or C₅₋₁₀aromatic, which can be substituted with 1, 2 or 3 R^(e).

R^(d) is independently for each occurrence H; C₁₋₆alkyl, which can besubstituted with 1, 2 or 3 R^(e) or a C₃₋₉ heterocyclyl; C₃₋₆cycloalkyl, which can be substituted with 1, 2 or 3 R^(e);C₃₋₆heterocyclic, which can be substituted with 1, 2 or 3 R^(e);C₅₋₁₀aryl, which can be substituted with 1, 2 or 3 R^(b);C₅₋₁₀heteroaryl, which can be substituted with 1, 2 or 3 R^(e); or twoR^(d) groups together with the nitrogen bound thereto provide aC₃₋₉heterocyclic, which can be substituted with one or more R^(e), or aC₅₋₁₀heteroaryl, which can be substituted with one or more R^(e).

R^(e) is independently for each occurrence halogen, C₁₋₆alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₅₋₁₀heteroaryl, or —OR^(a).

And R^(f) is independently for each occurrence -alkyl-phosphate, R^(a),R^(b), or R^(e), or two R^(f) groups together with the carbon atom boundthereto provide a C₂₋₆alkenyl group, a C₃₋₆cycloalkyl group, which canbe substituted with one or more R^(e), or a C₃₋₁₀heterocyclic, which canbe substituted with one or more R^(e) or acyl.

In certain embodiments of Formula ID, ring B is pyridinyl or pyrazolyl;L is a heteroatom or C₁₋₁₀aliphatic; Z is C₁₋₁₀aliphatic or aromatic;each R¹ is heterocyclyl, or C₁₋₁₀aliphatic; R² is H or C₁₋₁₀aliphatic;R³ together with the —N—C(O) moiety to which it is attached and two ringatoms from ring B forms a 5- or 6-membered heterocyclyl that is fused toring B— the heterocyclyl so formed is in certain embodimentsunsubstituted and in others is substituted by groups such as oxo, alkyland halo; each R⁴ independently is halogen or C₁₋₁₀aliphatic; m is 1, 2,3, or 4; and n is 0, 1 or 2.

In some embodiments of Formulas I, IA, IB, IC, ID and in eachcombination of Formulas I, IA, IB, IC and ID with the ring systemsillustrated in Formulas 1(a)-1(e), each R¹ independently isheterocyclyl, unsubstituted C₁₋₁₀aliphatic, or C₁₋₁₀aliphaticsubstituted with one or two substituents selected from —OH, halogen,carboxyl, carboxyl ester, heterocyclyl, amino, alkoxy, phosphate,cycloalkyl, alkenyl, —OC(O)NH(C₁₋₄ alkyl)-amino, —OC(O)R⁸, or—OC(O)(CHR⁹)₂CO₂H. The —OC(O)—R⁸ moiety is derived from an amino acidwhere the —OC(O)— moiety of —OC(O)—R⁸ corresponds to an acid moiety onthe amino acid and R⁸ comprises —N(R¹⁰)₂ or a nitrogen-containingnonaromatic heterocyclyl, where R¹⁰ is H or carboxyl ester. And each R⁹independently is H or —O-acyl.

With respect to the —OC(O)—R⁸ moiety, the nitrogen-containingnonaromatic heterocyclyl may be a 5- or 6-membered unsaturatednitrogen-containing heterocyclyl, for example, pyrrolidinyl. The aminoacid can be any amino acid, such as a naturally occurring amino acid,and may be an amino acid selected from glycine, valine, alanine,leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine,serine, threonine, asparagine, glutamine, arginine, histidine, lysine,aspartic acid, glutamic acid, cysteine, or proline. A person of ordinaryskill in the art will understand that where the amino acid comprises oneor more chiral center, all enantiomers, diastereomers and/or mixturesthereof are contemplated. For example, the amino acid may be the L-aminoacid, the D-amino acid or a mixture thereof. In some embodiments, theamino acid is the L-amino acid. And in certain embodiments, —OC(O)—R⁸ is—OC(O)CH(NH₂)R¹¹,

or —OC(O)—(CH₂)₁₋₂C(NH₂)CO₂H, where R¹¹ is an amino acid side chain,and/or may be H, —CH₃, isopropyl, —CH₂CH(CH₃)₂, —CH(CH₃)Et, —CH₂CH₂SCH₃,

—CH₂OH, —CH(OH)CH₃, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂SH,—CH₂CH₂CH₂NHC(O)(NH)NH₂,

CH₂CH₂CH₂CH₂NH₂, —CH₂CO₂H, or CH₂CH₂CO₂H.

Also with respect to R¹, at least one R¹ may be an 8- to 12-memberedspiroheterocyclyl or a C₁₋₁₀alkyne. The C₁₋₁₀alkyne may have one or twosubstituents. One substituent may be OH. In some embodiments, onesubstituent is oxetanyl, azetidinyl, pyridinyl, pyrrolidinyl,piperidinyl, tetrahydropyranyl, or phosphate, and/or in someembodiments, one substituent is —OC(O)—R⁸.

In some embodiments, m is 1, 2 or 3, and may be 1 or 2, and in certainembodiments, m is 1.

R² may be H or C₁₋₆alkyl, such as methyl.

R³ may be C₁₋₆alkyl, and, R³, together with the —N—C(O)— moiety to whichit is attached and two ring atoms from ring B, forms a 5- or 6-memberedheterocyclyl that is fused to ring B.

Each R⁴ independently may be halogen, such as F, Br, Cl or I, orC₁₋₁₀aliphatic, such as C₁₋₆alkyl. In some embodiments, each R⁴independently is chloro, fluoro or methyl.

In certain embodiments n is 0, and in other particular embodiments, n is1.

Also with respect to Formula I, L is a heteroatom or R^(a), providedthat R^(a) is not H or D. L may be oxygen or C₁₋₁₀alkyl, such asC₁₋₆alkyl, more particularly methylene (—CH₂—). Z is C₁₋₁₀aliphatic oraromatic, such as aryl or heteroaryl. In some embodiments, Z isC₃₋₆cycloalkyl, such as cyclobutyl or cyclopentyl, or C₁₋₆ alkyl, suchas methyl. In other embodiments, Z is heteroaryl, such as pyridinyl, orZ is

where each R⁵ independently is R^(e), and q is 0, 1, 2, 3, 4, or 5. Insuch embodiments, each R⁵ independently may be halogen or C₁₋₆alkyl,such as methyl or fluoro. In some embodiments, q is 1 or 2, but in otherembodiments, q is 0. And in certain embodiments, such as in Formulas I,IA, IB, IC and ID, the -L-Z moiety is phenoxy, 4-fluorophenoxy,3-fluorophenoxy, 2-fluorophenoxy, 2,4-difluorophenoxy,2,6-difluorophenoxy, 4-fluorobenzyl, 2,6-dimethylphenoxy, cyclobutyloxy,cyclopentyloxy, methoxy, 4-methylphenoxy, benzyl,(6-methylpyridin-2-yl)methyl or (6-fluoropyridin-2-yl)methyl.

In some embodiments of Formulas I, IA, IB, IC and ID, the compound mayhave a structure according to formulas I-1 or I-2:

In some embodiments, the compound may have a structure according to oneor more of the following formulas

With respect to Formulas I-1 to I-20, ring B, L, Z, R¹, R², R³, R⁴, mand n, if present, are as defined herein for Formula I. The ring formedby R³ together with the NC(O) moiety and two ring atoms from ring Bforms a heterocyclic ring that is fused to ring B. Examples of compoundsaccording to Formulas I-1 to I-20 have a structure according to one ofthe following formulas:

And with respect to Formulas I-21 to I-32, L, Z, R¹, R², R⁴, and n, areas defined herein for Formula I.

In any of the above embodiments concerning Formulas I, IA, IB, IC and IDand/or Formulas I-1 through I-32, R¹ may be selected from any of thefollowing:

And in certain embodiments, of Formula I and/or Formulas I-1 throughI-32, R¹ may be selected from any of the following:

In other embodiments of Formula I, disclosed compounds have Formula ID

ring B is 5-membered or 6-membered heteroaryl wherein R³ together withthe —N—C(O) moiety to which it is attached and two ring atoms from ringB form the 5- or 6-membered heterocyclyl that is fused to ring B;

L is a heteroatom or R^(a), provided that R^(a) is not H or D;

Z is C₁₋₁₀aliphatic (such as C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, orC₃₋₆cycloalkyl); or

R¹ is a halogen, —C═CH, or a -linker-R⁶ group, wherein the linker isR^(a), provided that R^(a) is not H or D, and R⁶ is R^(b), —C(R^(f))₃,or —C(R^(f))═C(R^(f))₂;

R² and R³ independently are R^(a);

R⁴ and R⁵ independently are R^(e);

-   -   R^(a) is independently for each occurrence H or D (except for        embodiments where L is R^(a)), C₁₋₁₀aliphatic (such as        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, or C₃₋₆cycloalkyl),        C₁₋₁₀haloaliphatic, C₅₋₁₀aromatic, or C₃₋₆ heterocyclic;    -   R^(b) is independently for each occurrence —OH, —SH, —OR^(c),        —SR^(c), —NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c), or        —C(O)NR^(d)R^(d);    -   R^(c) is independently for each occurrence C₁₋₁₀alkyl (which can        be substituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkenyl (which can be        substituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkynyl (which can be        substituted with 1, 2 or 3 R^(e)), C₃₋₆cycloalkyl (which can be        substituted with 1, 2 or 3 R^(e)), or C₅₋₁₀aromatic (which can        be substituted with 1, 2 or 3 R^(e));    -   R^(d) is independently for each occurrence H; C₁₋₆alkyl (which        can be substituted with 1, 2 or 3 R^(e)); C₃₋₆cycloalkyl (which        can be substituted with 1, 2 or 3 R^(e)); C₃₋₆heterocyclic        (which can be substituted with 1, 2 or 3 R^(e)); C₅₋₁₀aryl        (which can be substituted with 1, 2 or 3 R^(b)); C₅₋₁₀heteroaryl        (which can be substituted with 1, 2 or 3 R^(e)); or two R^(d)        groups together with the nitrogen bound thereto provide a        C₃₋₉heterocyclic (which can be substituted with one or more        R^(e)), or a C₅₋₁₀heteroaryl (which can be substituted with one        or more R^(e));    -   R^(e) is independently for each occurrence halogen, C₁₋₆alkyl,        C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₅₋₁₀heteroaryl, or —OR^(a); and    -   R^(f) is independently for each occurrence R^(a), R^(b), or        R^(e), or two R^(f) groups together with the carbon atom bound        thereto provide a C₃₋₆cycloalkyl group (which can be substituted        with one or more R^(e)), or a C₃₋₁₀heterocyclic (which can be        substituted with one or more R^(e));

m is 1 to 4, such as 1, 2, 3, or 4, with particular embodiments being 1or 2;

n is 0, 1 or 2; and

q is 0, 1, 2, 3, 4, or 5.

In some embodiments, a compound of the present disclosure can have astructure satisfying Formula IA

or a pharmaceutically acceptable salt thereof. A person of ordinaryskill in the art will appreciate that the disclosed general formulasinclude within their scope all stereoisomers, N-oxides, tautomers,hydrates, solvates, isotopes, and/or prodrugs of compounds otherwisehaving structural features required by such formulas.

With reference to Formula IA:

ring B is 5-membered or 6-membered heteroaryl wherein R³ together withthe —N—C(O) moiety to which it is attached and two ring atoms from ringB form the 5- or 6-membered heterocyclyl that is fused to ring B;

L is a heteroatom or R^(a), provided that R^(a) is not H or D;

R¹ is a halogen, —C═CH, or a -linker-R⁶ group, wherein the linker isR^(a), provided that R^(a) is not H or D, and R⁶ is R^(b), —C(R^(f))₃,or —C(R^(f))═C(R^(f))₂;

R² and R³ independently are R^(a);

R⁴ and R⁵ independently are R^(e);

-   -   R^(a) is independently for each occurrence H or D (except for        embodiments where L is R^(a)), C₁₋₁₀aliphatic (such as        C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, or C₃₋₆cycloalkyl),        C₁₋₁₀haloaliphatic, C₅₋₁₀aromatic, or C₃₋₆heterocyclic;    -   R^(b) is independently for each occurrence —OH, —SH, —OR^(c),        —SR^(c), —NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c), or        —C(O)NR^(d)R^(d);    -   R^(c) is independently for each occurrence C₁₋₁₀alkyl (which can        be substituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkenyl (which can be        substituted with 1, 2 or 3 R^(e)), C₂₋₁₀alkynyl (which can be        substituted with 1, 2 or 3 R^(e)), C₃₋₆cycloalkyl (which can be        substituted with 1, 2 or 3 R^(e)), or C₅₋₁₀aromatic (which can        be substituted with 1, 2 or 3 R^(e));    -   R^(d) is independently for each occurrence H; C₁₋₆alkyl (which        can be substituted with 1, 2 or 3 R^(e)); C₃₋₆cycloalkyl (which        can be substituted with 1, 2 or 3 R^(e)); C₃₋₆heterocyclic        (which can be substituted with 1, 2 or 3 R^(e)); C₅₋₁₀aryl        (which can be substituted with 1, 2 or 3 R^(b)); C₅₋₁₀heteroaryl        (which can be substituted with 1, 2 or 3 R^(e)); or two R^(d)        groups together with the nitrogen bound thereto provide a        C₃₋₉heterocyclic (which can be substituted with one or more        R^(e)), or a C₅₋₁₀heteroaryl (which can be substituted with one        or more R^(e));    -   R^(e) is independently for each occurrence halogen, C₁₋₆ alkyl,        C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,        C₅₋₁₀heteroaryl, or —OR^(a); and    -   R^(f) is independently for each occurrence R^(a), R^(b), or        R^(e) or two R^(f) groups together with the carbon atom bound        thereto provide a C₃₋₆cycloalkyl group (and in some embodiments,        the C₃₋₆cycloalkyl group is substituted with one or more R^(e)),        or a C₃₋₁₀heterocyclic (and in some embodiments, the        C₃₋₁₀heterocyclic group is substituted with one or more R^(e));

m is 1 to 4, such as 1, 2, 3, or 4, with particular embodiments being 1or 2;

n is 0, 1 or 2; and

q is 0, 1, 2, 3, 4, or 5.

In particular embodiments of Formulas I or IA, the 5-membered heteroarylgroup of the B ring can have structure satisfying formula

wherein at least one W is nitrogen, and each remaining W independentlyis selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. In someembodiments, the 5-membered heteroaryl group is a diazole, a triazole,an oxadiazole, or an oxazole. Exemplary triazoles include any of thefollowing:

Exemplary diazoles are selected from any of the following:

Exemplary oxazoles are selected from any of the following:

Exemplary oxadiazoles are selected from any of the following:

In particular embodiments of Formulas I, IA, IB, IC, ID or IE, L isoxygen or R^(a) wherein R^(a) is C₁-C₄alkyl, such as —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂—. In some embodiments, L is —CH₂— oroxygen.

The linker group of R¹ groups where R¹ is linker-R⁶ is a C₁, C₂, C₃, orC₄ aliphatic group, such a C₂ alkyl group, an alkenyl group, or analkynyl group, or a C₁, C₂, C₃, or C₄ haloaliphatic group, such as a C₂haloalkyl group, or an haloalkenyl group. In some embodiments, thelinker group of R¹ is R^(a) wherein R^(a) is C₁-C₄alkyl, such as —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂—; or the linker group isC₂-C₄alkenyl, such as —CH═CH—, —CH═CHCH₂—, —CH₂CH═CH—, or —CH₂CH═CHCH₂—;or the linker group is C₂-C₄alkynyl, such as —C≡C—, —C═C≡CH₂—, —CH₂C≡C—,or —CHC≡C—CH₂—. In some embodiments, the linker group isC₂-C₄haloalkenyl, such as —CF═CH—, —CCl═CH—, —CH═CCl—, —CH═CF—,—CCl═CCl—, —CF═CF—, or —CCl═CF—, —CF═CCl—. In some embodiments, linkergroup is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH═CH—,—CCl═CH—, —CH═CCl—, or —C≡C—.

The R⁶ group of R¹ is C(R^(f))₃ in some embodiments, wherein one R^(f)is R^(e), wherein R^(e) is —OR^(a) (e.g., hydroxyl or OMe) and eachother R^(f) independently is R^(a), wherein R^(a) is C₁₋₄aliphatic andpreferably each other R^(f) is R^(a) wherein R^(a) is independently foreach occurrence C₁₋₄alkyl. In particular embodiments, each other R^(f)is R^(a) wherein R^(a) is methyl or CD₃. In yet some additionalembodiments, R⁶ is —C(R^(f))₃ wherein each R^(f) is R^(a) wherein R^(a)is methyl or H or wherein each R^(f) is R^(a) wherein R^(a) is methyl orR^(b) wherein R^(b) is —C(O)OR^(c). In some additional embodiments, oneR^(f) is R^(e) is —OR^(a) (e.g., hydroxyl or OMe) and the other twoR^(f) groups join together to provide a alicyclic (e.g., cyclopropane,cyclobutane, cyclopentane, or cyclohexane) or heterocyclic group (e.g.,epoxide, oxetane, tetrahydrofuran, tetrahydropyran, orhexahydrofuro[3,2-b]furan) with the carbon atom to which they are bound.In some such embodiments, the alicyclic and/or heterocyclic group can besubstituted, with some particular embodiments being substituted with oneor more hydroxyl groups or benzyl-carbonyl groups.

Some compound embodiments have a linker group that is a C₂₋₄ group,which can comprise an alkyne. In particular embodiments, R¹ is a-linker-R⁶ group and the linker is R^(a) wherein R^(a) is —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH═CH—, or —C═C—, or —CH₂C═C—,and R⁶ is R^(b) wherein R^(b) is —C(O)OEt or is —C(O)NR^(d)R^(d) or—NR^(d)R^(d) wherein each R^(d) independently for each occurrence ishydrogen, C₅₋₁₀heteroaryl, C₃₋₆ cycloalkyl, or both R^(d) groups jointogether to provide a heterocyclic group with the nitrogen atom to whichthey are bound, which may further comprise one or more additionalheteroatoms aside from the nitrogen atom to which the R^(d) groups arebound. In some embodiments, one R^(d) is hydrogen and the other R^(d) isC₅₋₁₀heteroaryl, which can be substituted with one or more R^(e), suchas one of the following:

R⁶ also can be R^(b) wherein R^(b) is heterocyclyl, such as pyridinyl,which can be substituted or unsubstituted. In yet additionalembodiments, R⁶ can be R^(b) wherein R^(b) is —OH or —OR^(c) (whereinR^(c) is C₁₋₆alkyl and in some embodiments the C₁₋₆alkyl is substitutedwith C₅₋₁₀heteroaryl, such as pyridinyl; or wherein R^(c) isC₅₋₁₀heteroaryl, such as quinolinyl), or R^(b) can be —NR^(d)R^(d)wherein R^(d) is independently for each occurrence H, C₅₋₁₀heteroaryl(and in some embodiments, the C₅₋₁₀heteroaryl group is substituted withone or more R^(e) groups), or two R^(d) groups together with thenitrogen bound thereto provide a C₃₋₉heterocyclic (and in someembodiments, the C₃₋₉heterocyclic is substituted with one or more R^(e)groups) or a C₅₋₁₀heteroaryl (and in some embodiments, theC₅₋₁₀heteroaryl is substituted with one or more R^(e) groups). Inembodiments with R^(e) substitution, R^(e) independently for eachoccurrence C₅₋₁₀heteroaryl, or —OR^(a), wherein R^(a) is C₁₋₁₀alkyl.

Some compounds comprise a linker that is a C₁ group and an R⁶ group thatis R^(b), wherein R^(b) is —NR^(d)R^(d) wherein one R^(d) is H and theother R^(d) is pyridinyl, or wherein both R^(d) groups together with thenitrogen bound thereto provide a C₅₋₁₀heteroaryl; or R^(b) is OR^(c),wherein R^(c) is C₁₋₄alkyl substituted with a pyridinyl group. In someembodiments, R^(b) is

In some embodiments, R¹ can be selected from any of the following:

In some embodiments, each of R² and R³ independently is R^(a) whereinR^(a) is independently in each occurrence hydrogen, methyl, ethyl,propyl, butyl, pentyl, or hexyl. In particular embodiments, each of R²and R³ independently is R^(a) which is independently for each occurrencehydrogen, methyl, or ethyl. In exemplary embodiments, R² is methyl.

In some embodiments or, each R⁴ independently and/or each R⁵independently is R^(e), wherein R^(e) is alkyl, alkenyl, alkynyl,chloro, bromo, iodo, or fluoro. In particular embodiments, each R⁴and/or each R⁵ independently is R^(e) wherein R^(e) is lower aliphatic(e.g., methyl), fluoro, or chloro.

In some embodiments of Formulas I, IA, IB, IC, ID and IE, m is 1; n is 0or 1; p is 0 or 1; and q is 0, 1, or 2. In particular embodiments, m is1, n is 0, p is 0 or 1, and q is 0, 1, or 2.

The compounds of Formulas I or IA can also have structures satisfyingany one or more of Formulas II and IIA-IIF.

With reference to Formulas II and IIA-IIE, each of R¹ and R⁵ are asrecited above for Formulas I and/or IA. In particular embodiments, 0, 1,or 2 R⁵ groups are present. R⁵ can be R^(e) wherein R^(e) is fluoro orchloro. In other particular embodiments, R⁵ is not present. Withreference to Formulas IIA-IIE, each W independently is nitrogen oroxygen, and particularly nitrogen.Certain disclosed embodiments have a Formula IIF.

With reference to Formula IIF, R¹, R² and R³ are as stated above. R¹⁰ isalkyl, cyclic alkyl or aryl. More particularly R¹⁰ is lower alkyl, suchas C₁₋₁₀ alkyl, more particularly C₁₋₅ alkyl, including methyl, ethyl,propyl, butyl and pentyl. Cyclic alkyl groups are typically selectedfrom cyclobutyl, cyclopentyl, or cyclohexyl, particularly cyclobutyl orcyclopentyl. In some embodiments, compounds according to the presentdisclosure have a Formula IIG.

For many of the disclosed embodiments, R¹⁰ is phenyl. Accordingly,certain disclosed embodiments of the present disclosure have a FormulaIIH.

With reference to Formulas IIG an IIH, each of R¹ and R⁵ are as recitedabove for Formulas I and/or IA. R⁵ is R^(e). In particular embodiments,0, 1, or 2 R⁵ groups are present. In certain embodiments, R⁵ is notpresent or is halogen, such as fluoro or chloro, particularly fluoro, orC₁₋₆alkyl, such as methyl.

In some embodiments, the compounds of Formulas I, IA, IC, ID and IE alsocan have structures satisfying any one or more of Formulas III-VI:

With reference to Formulas III-VI, each R⁵ independently can be asrecited above and in some particular embodiments is lower aliphatic(e.g., methyl) or halogen, such as chloro or fluoro. Also, ring B is asrecited above and in some embodiments is selected from

R⁶ as illustrated in Formulas III-VI is as recited above and in someembodiments of Formulas I, IA, IB, IC, ID and IE is selected from one ofthe following:

Certain disclosed exemplary compounds within the scope of one or more ofFormulas I, I-1 to I-35, IA, II, IIA-IIJ, and III-VI include:

Exemplary compounds within the scope of one or more of Formulas I, IA,IB, IC, ID, IE, I-1 to I-32, IA, II, IIA-IIH, and III-VI include:

-   I-1:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-2:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-3:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((1-hydroxycyclopentyl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-4:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-4-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-5:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-3-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-6:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-7:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-(tert-butoxy)prop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-8:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-9:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-10:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-11:    (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-12:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-13:    (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-14:    (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-15:    (S)-6-((3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)ethynyl)picolinonitrile;-   I-16:    (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-17:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-18:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-19:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-20:    (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyrrolidin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;-   I-21:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-74(6-methylpyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;    =-   I-22:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;    or-   I-23:    (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;

In some embodiments, one or more of the compounds can be included in apharmaceutical composition or medicament, and in some embodiments thecompound or compounds can be in the form of the parent compound or apharmaceutically acceptable salt, a stereoisomer, an N-oxide, atautomer, a hydrate, a solvate, an isotope, or a prodrug thereof. Thepharmaceutical composition typically includes at least one additionalcomponent other than a disclosed compound or compounds, such as apharmaceutically acceptable excipient, an adjuvant, an additionaltherapeutic agent (described in the following section), or anycombination thereof.

Pharmaceutically acceptable excipients can be included in pharmaceuticalcompositions for a variety of purposes, such as to dilute apharmaceutical composition for delivery to a subject, to facilitateprocessing of the formulation, to provide advantageous materialproperties to the formulation, to facilitate dispersion from a deliverydevice, to stabilize the formulation (e.g., antioxidants or buffers), toprovide a pleasant or palatable taste or consistency to the formulation,or the like. The pharmaceutically acceptable excipient(s) may include apharmaceutically acceptable carrier(s). Exemplary excipients include,but are not limited to: mono-, di-, and polysaccharides, sugar alcoholsand other polyols, such as, lactose, glucose, raffinose, melezitose,lactitol, maltitol, trehalose, sucrose, mannitol, starch, orcombinations thereof; surfactants, such as sorbitols, diphosphatidylcholine, and lecithin; bulking agents; buffers, such as phosphate andcitrate buffers; anti-adherents, such as magnesium stearate; binders,such as saccharides (including disaccharides, such as sucrose andlactose), polysaccharides (such as starches, cellulose, microcrystallinecellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin,synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols);coatings (such as cellulose ethers, including hydroxypropylmethylcellulose, shellac, corn protein zein, and gelatin); release aids (suchas enteric coatings); disintegrants (such as crospovidone, crosslinkedsodium carboxymethyl cellulose, and sodium starch glycolate); fillers(such as dibasic calcium phosphate, vegetable fats and oils, lactose,sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesiumstearate); flavors and sweeteners (such as mint, cherry, anise, peach,apricot or licorice, raspberry, and vanilla; lubricants (such asminerals, exemplified by talc or silica, fats, exemplified by vegetablestearin, magnesium stearate or stearic acid); preservatives (such asantioxidants exemplified by vitamin A, vitamin E, vitamin C, retinylpalmitate, and selenium, amino acids, exemplified by cysteine andmethionine, citric acid and sodium citrate, parabens, exemplified bymethyl paraben and propyl paraben); colorants; compression aids;emulsifying agents; encapsulation agents; gums; granulation agents; andcombinations thereof.

B. Combinations of Therapeutic Agents

The compounds described herein may be used alone, in combination withone another, in separate pharmaceutical compositions, together in asingle pharmaceutical composition, or as an adjunct to, or incombination with, other established therapies. The compound or compoundsor composition comprising the compound (or compounds) may beadministered once, or in plural administrations. In some embodiments,the compounds of the present disclosure may be used in combination withother therapeutic agents useful for the disorder or condition beingtreated. These other therapeutic agents may be administeredsimultaneously, sequentially in any order, by the same route ofadministration, or by a different route as the presently disclosedcompounds. For sequential administration, the compound(s) and thetherapeutic agent(s) may be administered such that an effective timeperiod of at least one compound and the therapeutic agent overlaps withan effective time period of at least one other compound and/ortherapeutic agent. In an exemplary embodiment of a combinationcomprising four components, the effective time period of the firstcomponent administered may overlap with the effective time periods ofthe second, third and fourth components, but the effective time periodsof the second, third and fourth components independently may or may notoverlap with one another. In another exemplary embodiment of acombination comprising four components, the effective time period of thefirst component administered overlaps with the effective time period ofthe second component, but not that of the third or fourth; the effectivetime period of the second component overlaps with those of the first andthird components; and the effective time period of the fourth componentoverlaps with that of the third component only. In some embodiments, theeffective time periods of all compounds and/or therapeutic agentsoverlap with each other.

In some embodiments, the compounds are administered with anothertherapeutic agent, such as an analgesic, an antibiotic, ananticoagulant, an antibody, an anti-inflammatory agent, animmunosuppressant, a guanylate cyclase-C agonist, an intestinalsecretagogue, an antiviral, anticancer, antifungal, or a combinationthereof. The anti-inflammatory agent may be a steroid or a nonsteroidalanti-inflammatory agent. In certain embodiments, the nonsteroidalanti-inflammatory agent is selected from aminosalicylates,cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen,flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin,meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen,oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combinationthereof. In some embodiments, the immunosuppressant is mercaptopurine, acorticosteroid, an alkylating agent, a calcineurin inhibitor, an inosinemonophosphate dehydrogenase inhibitor, antilymphocyte globulin,antithymocyte globulin, an anti-T-cell antibody, or a combinationthereof. In one embodiment, the antibody is infliximab.

In some embodiments, the present compounds may be used with anti-canceror cytotoxic agents. Various classes of anti-cancer and anti-neoplasticcompounds include, but are not limited to, alkylating agents,antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes,antibiotics, enzymes, cytokines, platinum coordination complexes,proteasome inhibitors, substituted ureas, kinase inhibitors, hormonesand hormone antagonists, and hypomethylating agents, for example DNMTinhibitors, such as azacitidine and decitabine. Exemplary alkylatingagents include, without limitation, mechlorothamine, cyclophosphamide,ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines,alkyl sulfonates (e.g., busulfan), and carmustine. Exemplaryantimetabolites include, by way of example and not limitation, folicacid analog methotrexate; pyrimidine analog fluorouracil, cytosinearbinoside; purine analogs mercaptopurine, thioguanine, andazathioprine. Exemplary vinca alkyloids include, by way of example andnot limitation, vinblastine, vincristine, paclitaxel, and colchicine.Exemplary antibiotics include, by way of example and not limitation,actinomycin D, daunorubicin, and bleomycin. An exemplary enzymeeffective as an anti-neoplastic agent includes L-asparaginase. Exemplarycoordination compounds include, by way of example and not limitation,cisplatin and carboplatin. Exemplary hormones and hormone relatedcompounds include, by way of example and not limitation,adrenocorticosteroids prednisone and dexamethasone; aromatase inhibitorsamino glutethimide, formestane, and anastrozole; progestin compoundshydroxyprogesterone caproate, medroxyprogesterone; and anti-estrogencompound tamoxifen.

These and other useful anti-cancer compounds are described in MerckIndex, 13th Ed. (O'Neil M. J. et al., ed.) Merck Publishing Group (2001)and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12thEdition, Brunton L. L. ed., Chapters 60-63, McGraw Hill, (2011), both ofwhich are incorporated by reference herein.

Among the CTLA 4 antibodies that can be used in combination with thepresently disclosed inhbitors is ipilimumab, marketed as YERVOY® byBristol-Myers Squibb.

Other chemotherapeutic agents for combination include immunooncologyagents, such as checkpoint pathway inhibitors, for example, PD-1inhibitors, such as nivolumab and lambrolizumab, and PD-L1 inhibitors,such as pembrolizumab, MEDI-4736 and MPDL3280A/RG7446. Additionalcheckpoint inhibitors for combination with the compounds disclosedherein include, Anti-LAG-3 agents, such as BMS-986016 (MDX-1408).

Further chemotherapeutic agents for combination with the presentlydisclosed inhibitors include Anti-SLAMF7 agents, such as the humanizedmonoclonal antibody elotuzumab (BMS-901608), anti-KIR agents, such asthe anti-KIR monoclonal antibody lirilumab (BMS-986015), and anti-CD137agents, such as the fully human monoclonal antibody urelumab(BMS-663513), anti-CD123 agents, such as tagraxofusperzs, marketed underthe trade name, Elzonris.

The presently disclosed compounds also may be used advantageously withCAR-T therapies. Example of currently available CAR-T therapies areaxicabtagene ciloleucel and tisagenlecleucel.

Use of the present compounds in combination with other therapies isparticularly useful in treating hyperproliferative disorders. Thepresent compounds can be used to treat disorders such as cancers,leukemias and lymphomas in combination with the standard of care. By wayof example, myelodysplastic syndrome (MDS) can be treated with acompound disclosed herein along with the standard of care. Therapeuticsfor use in combination with the present compounds includehypomethylating agents, such as azacitidine and decitabine, and otherchemotherapeutic agents, such as cytarabine, daunorubicin andidarubicin. Immunomodulatory therapies, such as lenalidomide and CAR-Ttherapies, also can be used in combination with the present compoundsfor treating MDS.

Additional anti-proliferative compounds useful in combination with thecompounds of the present disclosure include, by way of example and notlimitation, antibodies directed against growth factor receptors (e.g.,anti-Her2); and cytokines such as interferon-α and interferon-γ,interleukin-2, and GM-CSF.

Additional chemotherapeutic agents useful in combination with thepresent compounds include proteasome inhibitors, such as bortezomib,carfilzomib, marizomib and the like.

Examples of kinase inhibitors that are useful in combination with thepresently disclosed compounds, particularly in treating malignanciesinclude: Btk inhibitors, such as ibrutinib; CDK inhibitors, such aspalbociclib; EGFR inhibitors, such as afatinib, erlotinib, gefitinib,lapatinib, osimertinib and vandetinib; Mek inhibitors, such astrametinib; Raf inhibitors, such as dabrafenib, sorafenib andvemurafenib; VEGFR inhibitors, such as axitinib, lenvatinib, nintedanib,pazopanib; BCR-Abl inhibitors, such as bosutinib, dasatinib, imatiniband nilotinib; FLT-3 inhibitors, such as gilteritinib and quizartinib,PI3-kinase inhibitors, such as idelalisib, Syk inhibitors, such asfostamatinib; and JAK inhibitors, such as ruxolitinib and fedratinib.

In other embodiments, the second therapeutic agent may be selected fromany of the following:

analgesics-morphine, fentanyl, hydromorphone, oxycodone, codeine,acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine,flupirtine, meperidine, pentazocine, dextromoramide, dipipanone;

antibiotics-aminoglycosides (e.g., amikacin, gentamicin, kanamycin,neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g.,ertapenem, doripenem, imipenem, cilastatin, and meropenem),cephalosporins (e.g., cefadroxil, cefazolin, cefalotin, cephalexin,cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime,cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, andcefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, andtelavancin), lincosamides (e.g., clindamycin and incomysin),lipopeptides (e.g., daptomycin), macrolides (azithromycin,clarithromycin, dirithromycin, erythromycin, roxithromycin,troleandomycin, telithromycin, and spectinomycin), monobactams (e.g.,aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin),penicillins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin,cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin,nafcillin, oxacillin, penicillin G, penicillin V, piperacillin,temocillin, and ticarcillin), penicillin combinations (e.g.,amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam,and ticarcillin/clavulanate), polypeptides (e.g., bacitracin, colistin,and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin,gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid,norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, andtemafloxacin), sulfonamides (e.g., mafenide, sulfonamidochrysoidine,sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole,sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole,trimethoprim, and trimethoprim-sulfamethoxaxzole), tetracyclines (e.g.,demeclocycline, doxycycline, minocycline, oxytetracycline, andtetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone,capreomycin, cycloserine, ethambutol, ethionamide, isoniazid,pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, andstreptomycin), and others, such as arsphenamine, chloramphenicol,fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin,platensimycin, quinuprisin/dalfopristin, rifaximin, thiamphenicol,tigecycline, and timidazole;

antibodies-anti-TNF-α antibodies, e.g., infliximab (Remicade™),adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g.,rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1antibodies, e.g., anakinra; anti PD-1 and/or anti-PD-L1 antibodies, e.g.nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224,MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab,clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab,sarilumab, secukinumab, toralizumab, zanolimumab;

anticoagulants-warfarin (Coumadin™), acenocoumarol, phenprocoumon,atromentin, phenindione, heparin, fondaparinux, idraparinux,rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam,dabigatran, ximelagatran, batroxobin, hementin;

anti-inflammatory agents-steroids, e.g., budesonide, nonsteroidalanti-inflammatory agents, e.g., aminosalicylates (e.g., sulfasalazine,mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors(COX-2 inhibitors, such as rofecoxib, celecoxib), diclofenac, etodolac,famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen,indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone,naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin;

immunosuppressants-mercaptopurine, corticosteroids such asdexamethasone, hydrocortisone, prednisone, methylprednisolone andprednisolone, alkylating agents such as cyclophosphamide, calcineurininhibitors such as cyclosporine, sirolimus and tacrolimus, inhibitors ofinosine monophosphate dehydrogenase (IMPDH) such as mycophenolate,mycophenolate mofetil and azathioprine, and agents designed to suppresscellular immunity while leaving the recipient's humoral immunologicresponse intact, including various antibodies (for example,antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonalanti-T-cell antibodies (OKT3)) and irradiation. Azathioprine iscurrently available from Salix Pharmaceuticals, Inc. under the brandname Azasan; mercaptopurine is currently available from GatePharmaceuticals, Inc. under the brand name Purinethol; prednisone andprednisolone are currently available from Roxane Laboratories, Inc.;Methyl prednisolone is currently available from Pfizer; sirolimus(rapamycin) is currently available from Wyeth-Ayerst under the brandname Rapamune; tacrolimus is currently available from Fujisawa under thebrand name Prograf; cyclosporine is current available from Novartisunder the brand name Sandimmune and Abbott under the brand name Gengraf;IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid arecurrently available from Roche under the brand name Cellcept andNovartis under the brand name Myfortic; azathioprine is currentlyavailable from Glaxo Smith Kline under the brand name Imuran; andantibodies are currently available from Ortho Biotech under the brandname Orthoclone, Novartis under the brand name Simulect (basiliximab)and Roche under the brand name Zenapax (daclizumab); and

Guanylate cyclase-C receptor agonists or intestinal secretagogues, forexample linaclotide, sold under the name Linzess.

These various agents can be used in accordance with their standard orcommon dosages, as specified in the prescribing information accompanyingcommercially available forms of the drugs (see also, the prescribinginformation in the 2006 Edition of The Physician's Desk Reference), thedisclosures of which are incorporated herein by reference.

III. Methods of Making Compounds

Disclosed embodiments of the present compounds can be prepared by anysuitable method as will be understood by a person of ordinary skill inthe art. One exemplary suitable method is provided below with referenceto specific compounds in the examples, and can include the followingfirst reaction step according to Scheme 1.

With reference to Scheme 1, protected amine precursor 100 can be coupledwith R¹ group 102, which comprises an “R⁶-linker” group as illustratedin Scheme 1, using a metal-mediated, cross-coupling reaction to providethe cross-coupled product 104. In some embodiments, the metal-mediated,cross-coupling reaction can be carried out using a transition metalcatalyst, such as a palladium catalyst. Exemplary palladium catalystsinclude, but are not limited to, Pd(0) catalysts (e.g., Pd₂(dba)₃,Pd(dba)₂, Pd(PPh₃)₄, and the like) or Pd(II) catalyst (e.g., XPhos Pdgeneration 2 or generation 3, PdCl₂, Pd(OAc)₂, and the like). In someembodiments, the palladium catalyst can be used in combination withanother co-catalyst, such as CuI, to promote the cross-couplingreaction, such as in a Sonogoshira reaction. The metal-mediated,cross-coupling also can comprise using a base, such as an amine base(e.g., Et₃N), or an inorganic base (e.g., Cs₂CO₃, Na₂CO₃, K₂CO₃ or thelike), and a solvent (e.g., dimethylformamide). With reference to Scheme1, X is a suitable group for metal-mediated, cross-coupling, such as ahalogen or a triflate group and PG is an amine protecting group, whichcan be selected from, but is not limited to, a9-fluorenylmethoxycarbonyl (“Fmoc”) group, a t-butyloxycarbonyl (“Boc”)group, a trityl (“Tr”) group, an allyloxycarbonyl (“Alloc”) group, abenzyloxycarbonyl (“Cbz”) group, and the like.

Representative examples of the method steps shown in Scheme 1 areprovided below in Schemes 2A-2F. A method similar to that illustrated inScheme 2A can be used to make compounds I-14 to I-17 and I-35 byreplacing the propargylic alcohol in Scheme 2A with the correspondingalkyne group that gives rise to each of compounds I-14 to I-17 and I-35;the further modifications that can be used to arrive at the finalstructure of compounds I-14 to I-17 are discussed below.

Once cross-coupled product 104 is made, it can be subjected to anoptional linker group reduction step wherein linker groups comprisingone or more sites of unsaturation can be reduced to saturated linkergroups and/or linker groups having fewer degrees of unsaturation. If alinker reduction group is used, it can then be followed by adeprotection step and then an amide formation step, as illustrated inScheme 3. Alternatively, if a linker group reduction step is not used,then cross-coupled product 104 can be deprotected and converted to amidecompound 302.

With reference to Scheme 3, an optional linker reduction step can becarried out. For example, if the linker comprises a site of unsaturation(e.g., a double or triple bond), the site of unsaturation can be reducedsuch that it becomes fully saturated (e.g., such as reducing a doublebond and/or a triple bond to a single bond) or that it has few degreesof unsaturation (e.g., such as reducing a triple bond to a double bond).Suitable reagents for carrying out such an optional linker reductionstep are recognized by those of ordinary skill in the art with thebenefit of the present disclosure; however, one exemplary set ofconditions includes exposing cross-coupled product 104 to H₂ in thepresence of Pd on carbon. As these steps are optional, they need not becarried out in all embodiments. Instead, in some embodiments,cross-coupled product 104 can be deprotected to provide an amine that isthen converted to amide compound 302 by reacting the amine with asuitable acid coupling partner 300, as illustrated in Scheme 3. In someembodiments, the method can further comprise making one or moreadditional modifications to amide compound 302 to provide amide compound500, such as modifying an R⁶ group to form a different R⁶ group, asillustrated in Scheme 4.

With reference to Scheme 5, one or more modifications to the R⁶ groupcan be carried out. For example, if R⁶ is an ester group, it can beconverted to a carboxylic acid or to a primary alcohol. Suitablereagents for carrying out such an optional modification step arerecognized by those of ordinary skill in the art with the benefit of thepresent disclosure; however, one exemplary set of conditions includesexposing an R⁶ ester group to LiOH to provide the corresponding acid.

A number of the exemplary disclosed compounds are alkynyl substitutedanalogs. These compounds can be made using a metal-mediated couplingstrategy as discussed above with reference to Scheme 1. Scheme 5illustrates a more detailed general method for making alkynylsubstituted analogs according to the present disclosure.

With reference to Scheme 5, nitrogen was bubbled through a stirringsolution of an aryl/hetetoarylhalide (1 equivalent), either compound 700or 706, CuI (0.1-0.2 equivalent), and Pd(PPh₃)₄ (0.05-0.1 equivalent) indry DMF (3-4 mL/mmol) for 3 minutes in a vial. Subsequently, to the darkreaction solution was added NEt₃ (10 equivalents), followed by thecorresponding alkyne (1.5-3 equivalents), either compound 702 or 708, inquick succession. Nitrogen was bubbled through the reaction mixture for2 minutes, and the vial capped. The reaction mixture was stirred at aneffective reaction temperatures, such as 70-90° C., for an effectivereaction period, such as 3-6 hours. Alternatively, the reaction mixturecan be heated in a microwave reactor (30-45 minutes) until thearyl/hetetoarylhalide 700 or 706 was consumed. The dark reactionsolution was processed by one of the following methods: a) a work-up ofdiluting with ice-water/organic solvent; b) concentrated to dryness,followed by a work-up after diluting with ice-water/organic solvent; orc) the crude residue was diluted with ice-water, sonicated and theslurry allowed to warm to room temperature. The resulting grey/darksolid was collected by filtration, suction dried, dissolved in THF (20mL), filtered through Celite®/silica gel pad, and the pad was washedwith THF. Subsequently, the crude material was purified by reverse phasecolumn chromatographic or by normal phase silica gel flash columnchromatography to provide corresponding the alkynyl substituted analogs(Yield: 25-69%), compounds 704 or 710.

IV. Methods of Using Compounds

A. Diseases/Disorders

The disclosed compounds, as well as combinations and/or pharmaceuticalcompositions thereof, may be used to inhibit a RIP1 kinase by contactingthe kinase either in vivo or ex vivo, with a compound or compounds ofthe present disclosure, or a composition comprising a compound orcompounds of the present disclosure. Disclosed compound or compounds, orcompositions comprising a disclosed compound or compounds also can beused to ameliorate, treat or prevent a variety of diseases and/ordisorders. In particular embodiments, the disclosed compound,combinations of disclosed compounds, or pharmaceutical compositionsthereof, may be useful for treating conditions in which inhibition ofRIP1 or a pathway involving RIP1 is therapeutically useful. In someembodiments, the compounds directly inhibit RIP1 kinase activity.Examples of diseases that can be treated according to this methodembodiment include diseases or disorders associated with inflammation,necroptosis, or both. In certain embodiments, diseases to be treatedwith the present compounds are inflammatory or immune-regulatorydisorders, including autoimmune and proliferative disorders.

In an embodiment, the disease to be treated with a compound or compoundsaccording to the present invention, or a composition comprising acompound or compounds according to the present invention, is selectedfrom amyotrophic lateral sclerosis (ALS), rheumatoid arthritis, type Idiabetes mellitus, inflammatory bowel diseases, including Crohn'sdisease and ulcerative colitis, biliary cirrhosis, multiple sclerosis,bullous pemphigoid, psoriasis, autoimmune myositis, Wegener'sgranulomatosis, ichthyosis, asthma, spondyloarthritis, SoJIA, or Still'sdisease, autoimmune hepatitis, autoimmune hepatobiliary diseases,autoimmune ITP, cerebrovascular accident, myocardial infarction,allergic diseases, chronic obstructive pulmonary disease, cardiacinfarction, HIV-associated dementia, glaucoma, Friedreich's ataxia, Lewybody disease, spinal cord injury, diabetic neuropathy, polyglutamine(polyQ) diseases, stroke, Fahr disease, Menke's disease, Wilson'sdisease, cerebral ischemia, prion disorder, destructive bone disorderssuch as bone resorption disease, multiple myeloma-related bone disorder;proliferative disorders such as hyperproliferative skin disorders andhematological disorders, such as lymphomas, for example, Hodgkinslymphoma and non-Hodgkins lymphoma, ABC diffuse large B-cell lymphoma(DLBCL), Waldenström's macroglobulinemia, primary cutaneous T-celllymphoma or chronic lymphocytic leukemia, smoldering or indolentmultiple myeloma, or hematological malignancies, leukemia, acute myeloidleukemia (AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL),chronic lymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS),myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenström'smacroglobulinemia (WM), splenic marginal zone lymphoma, multiplemyeloma, plasmacytoma, intravascular large B-cell lymphoma, drugresistant malignancies, such as JAK inhibitor-resistant malignancies andibrutinib resistant malignancies, for example ibrutinib resistanthematological malignancies, ibrutinib resistant CLL and ibrutinibresistant Waldenström's macroglobulinemia, acute myelogenous leukemia,chronic myelogenous leukemia; angiogenic disorders such as angiogenicdisorders including solid tumors, ocular neovascularization,hemangiomas, such as infantile hemangiomas; infectious diseases such assepsis, septic shock, and shigellosis; neurodegenerative diseases suchas metastatic melanoma, neurodegeneration associated with HIV infectionand CMV retinitis, such as associated neurocognitive disorders ordementia, fibrotic conditions such as, nonalcoholic steatohepatitis andcardiac conditions such as, ischemia reperfusion; allergies, adultrespiratory distress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, erythematosis, chronic thyroiditis, Graves' disease,autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graftversus host disease, inflammatory reaction induced by endotoxin,tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter'ssyndrome, rubella arthritis, acute synovitis, pancreatic β-cell disease;diseases characterized by massive neutrophil infiltration; rheumatoidspondylitis, gouty arthritis, psoriatic arthritis, and other arthriticconditions, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoidosis, allograft rejections, fever andmyalgias due to infection, keloid formation, scar tissue formation,ulcerative colitis, pyresis, influenza, chronic myelogenous leukemia;angiogenic disorders including solid tumors; viral diseases includingacute hepatitis infection (including hepatitis A, hepatitis B andhepatitis C), AIDS, ARC or malignancy, herpes; stroke, myocardialischemia, ischemia in stroke heart attacks, organ hypoxia, vascularhyperplasia, cardiac and renal reperfusion injury, cardiac hypertrophy,thrombin-induced platelet aggregation, endotoxemia and/or toxic shocksyndrome, conditions associated with prostaglandin endoperoxidasesyndase-2, pemphigus vulgaris, ischemia reperfusion injury, includingcerebral ischemia reperfusions injury arising from stroke, cardiacischemia reperfusion injury arising from myocardial infarction, multiplesystem atrophy, Parkinson-plus syndromes, frontotemporal dementia,intracranial hemorrhage, cerebral hemorrhage, progressive muscularatrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscularatrophy, inherited muscular atrophy, peripheral neuropathies,progressive supranuclear palsy, corticobasal degeneration, demyelinatingdiseases, spondylarthritis, systemic onset juvenile idiopathic arthritis(SoJIA), systemic lupus erythematosus (SLE), Sjogren's syndrome,anti-phospholipid syndrome (APS), primary sclerosing cholangitis (PSC),renal transplant, surgery, acute kidney injury (AKI), systemicinflammatory response syndrome (SIRS), cytokine release syndrome (CRS),acute respiratory distress syndrome (ARDS), ARDS resulting fromCOVID-19, cerebrovascular accident (CVA), pulmonary sarcoidosis,interleukin-1 converting enzyme (ICE, also known as caspase-1)associated fever syndrome, chronic obstructive pulmonary disease (COPD),periodontitis, NEMO-deficiency syndrome (F-kappa-B essential modulatorgene (also known as IKK gamma or IKKG) deficiency syndrome),hematological and solid organ malignancies, lysosomal storage diseases,glaucoma, spondyloarthritis, retinal degenerative disease, retinalischemia/reperfusion injury, renal ischemia reperfusion injury, anthraxlethal toxin induced septic shock, cell death induced by LPS, infectiousencephalopathy, encephalitis, autoimmune uveoretinitis, giant cellarteritis, regional enteritis, granulomatous enteritis, distal ileitis,regional ileitis, terminal ileitis, insulin-dependent diabetes mellitus,scleroderma, systemic lupus erythematosus, macular edema, diabeticretinopathy, central areolar choroidal dystrophy, BEST disease, adultvitelliform disease, pattern dystrophy, myopic degeneration, centralserous retinopathy, Stargardt's disease, Cone-Rod dystrophy, NorthCarolina dystrophy, infectious retinitis, inflammatory retinitis,uveitis, toxic retinitis and light-induced toxicity, macular edema,diabetic retinopathy, central areolar choroidal dystrophy, BEST disease,adult vitelliform disease, pattern dystrophy, optic nerve injury, opticneuritis, optic neuropathies, diabetic retinopathy, central retinalartery occlusion, ischemic optic neuropathy (e.g., arteritic ornon-arteritic anterior ischemic neuropathy and posterior ischemic opticneuropathy), compressive optic neuropathy, infiltrative opticneuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy(e.g., Leber's optic neuropathy), nutritional optic neuropathy, toxicoptic neuropathy and hereditary optic neuropathy, Dominant OpticAtrophy, Behr's syndrome, Creutzfeldt-Jakob disease), progressivesupranuclear palsy, hereditary spastic paresis, subarachnoid hemorrhage,perinatal brain injury, subclinical brain injury, spinal cord injury,anoxic-ischemic brain injury, focal cerebral ischemia, global cerebralischemia, and hypoxic hypoxia, peritoneal damage caused by peritonealdialysis fluid (PDF) and PD-related side effects, glomerular diseases,tubulointerstitial diseases, obstruction, polycystic kidney disease),focal glomerulosclerosis, immune complex nephropathy, hepatocellularcancer, pancreatic cancer, urological cancer, bladder cancer, colorectalcancer, colon cancer, breast cancer, prostate cancer, renal cancer,thyroid cancer, gall bladder cancer, peritoneal cancer, ovarian cancer,cervical cancer, gastric cancer, endometrial cancer, esophageal cancer,head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors(e.g., glioma, anaplastic oligodendroglioma, adult glioblastomamultiforme, and adult anaplastic astrocytoma), bone cancer, soft tissuesarcoma, retinoblastomas, neuroblastomas, peritoneal effusions,malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblasticneoplasms, hemangiopericytomas, myxoid carcinoma, round cell carcinoma,squamous cell carcinomas, esophageal squamous cell carcinomas, oralcarcinomas, vulval cancer, cancers of the adrenal cortex, ACTH producingtumors, lymphoma, and leukemia, respiratory infectious viruses, such asinfluenza virus, rhino virus, corona virus, parainfluenza virus, RSvirus, adeno virus, reo virus and the like), herpes zoster caused byherpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS,bacterial infectious diseases, such as Bacillus cereus, Vibrioparahaemolyticus, Enterohemorrhagic Escherichia coli, Staphylococcusaureus, MRS A, Salmonella, Botulinus, Candida, Paget's disease,achondroplasia, osteochodrytis, hyperparathyroidism, osteogenesisimperfecta, congenital hypophosphatasia, fibromatous lesions, fibrousdisplasia, bone turnover, osteolytic bone disease, periodontal disease,treating post-traumatic bone surgery, treating post-prosthetic jointsurgery, treating post-plastic bone surgery, treating post-dentalsurgery, bone chemotherapy treatment or bone radiotherapy treatment,bone cancer, fragile plaque, disorder, occlusive disorder, stenosis,coronary artery disorders, peripheral arterial disorders, arterialocclusion, aneurysm formation, post-traumatic aneurysm formation,restenosis, post-operative graft occlusion, autoimmune idiopathicthrombocytopenic purpura (autoimmune ITP), membranous nephritis,autoimmune thyroiditis, cold and warm agglutinin diseases, Evan'ssyndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura(HUS/TTP), and pemphigus vulgaris.

In another embodiment, the disease to be treated with a compound orcompounds according to the present invention, or a compositioncomprising a compound or compounds according to the present invention,is selected from amyotrophic lateral sclerosis (ALS), spinal muscularatrophy, systemic lupus erythematosus, rheumatoid arthritis, type Idiabetes mellitus, inflammatory bowel diseases, Crohn's disease,ulcerative colitis biliary cirrhosis, uveitis, multiple sclerosis,bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis,Wegener's granulomatosis, ichthyosis, Graves ophthalmyopathy, asthma,bone marrow rejection, organ transplant rejection, graft-versus-hostdisease, inflammatory and immune regulatory disorders, transplantationof organs or tissue, graft-versus-host diseases brought about bytransplantation, autoimmune syndromes, rheumatoid arthritis, systemiclupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis,systemic sclerosis, systemic inflammatory response syndrome, myastheniagravis, type I diabetes, uveitis, posterior uveitis, allergicencephalomyelitis, glomerulonephritis, postinfectious autoimmunediseases, rheumatic fever, post-infectious glomerulonephritis,inflammatory and hyperproliferative skin diseases, psoriasis, atopicdermatitis, contact dermatitis, eczematous dermatitis, seborrhoeicdermatitis, pustular psoriasis, lichen planus, pemphigus, bullouspemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitis,erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopeciaareata, keratoconjunctivitis, vernal conjunctivitis, uveitis associatedwith Behcet's disease, keratitis, herpetic keratitis, conical cornea,dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus,Mooren's ulcer, scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Haradasyndrome, sarcoidosis, pollen allergies, reversible obstructive airwaydisease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsicasthma, dust asthma, chronic or inveterate asthma, late asthma andairway hyper-responsiveness, bronchitis, gastric ulcers, vascular damagecaused by ischemic diseases and thrombosis, ischemic bowel diseases,ischemia-reperfusion injuries, inflammatory bowel diseases, necrotizingenterocolitis, intestinal lesions associated with thermal burns, celiacdiseases, proctitis, eosinophilic gastroenteritis, mastocytosis,ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy,multiple myositis, Guillain-Barre syndrome, Meniere's disease,polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis or myocardial infarction, scleroderma, systemicscleroderma, anti-phospholipid syndrome, Wegener's granuloma, Sjögren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia, alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, retinaldegeneration, retinal detachment, senile macular degeneration, vitrealscarring, corneal alkali burn, dermatitis erythema multiforme, linearIgA bullous dermatitis, cement dermatitis, gingivitis, periodontitis,sepsis, pancreatitis, diseases caused by environmental pollution, aging,carcinogenesis, metastasis of carcinoma and hypobaropathy, diseasecaused by histamine or leukotriene-C4 release, Behcet's disease,autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis,partial liver resection, acute liver necrosis, necrosis caused by toxin,necrosis caused by viral hepatitis, necrosis caused by shock, necrosiscaused by anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis,alcoholic liver disease, alcoholic cirrhosis, alcoholic steatohepatitis,non-alcoholic steatohepatitis (NASH), autoimmune hepatobiliary diseases,acetaminophen toxicity, hepatotoxicity, hepatic failure, fulminanthepatic failure, late-onset hepatic failure, “acute-on-chronic” liverfailure, chronic kidney diseases, kidney damage/injury, kidneydamage/injury caused by nephritis, kidney damage/injury caused by renaltransplant, kidney damage/injury caused by surgery, kidney damage/injurycaused by administration of nephrotoxic drugs, kidney damage/injurycaused by acute kidney injury, augmentation of chemotherapeutic effect,cytomegalovirus infection, HCMV infection, AIDS, cancer, seniledementia, Parkinson's disease, trauma, or chronic bacterial infection,interleukin-1 converting enzyme-associated associated fever syndrome,tumor necrosis factor receptor-associated periodic syndrome,NEMO-deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chainassembly complex deficiency syndrome, lysosomal storage diseases,Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis,aspartylglucosaminuria, cholesteryl ester storage disease, chronichexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease,Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis,mucolipidosis, infantile free sialic acid storage disease, juvenilehexosaminidase A deficiency, Krabbe disease, lysosomal acid lipasedeficiency, metachromatic leukodystrophy, mucopolysaccharidosesdisorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronalceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease,Schindler disease, sialic acid storage disease, Tay-Sachs disease,Wolman disease, Huntington's disease, Parkinson's disease, benign andmalignant tumors, solid tumors, carcinoma of the brain carcinoma, kidneycarcinoma, liver carcinoma, adrenal gland carcinoma, bladder carcinoma,breast carcinoma, stomach carcinoma, carcinoma of the gastric tumors,carcinoma of the ovaries, colon carcinoma, rectum carcinoma, prostatecarcinoma, carcinoma of the pancreas, lung carcinoma, carcinoma of thevagina, carcinoma of the cervix, carcinoma of the testis, carcinoma ofthe genitourinary tract, carcinoma of the esophagus, carcinoma of thelarynx, carcinoma of the skin, carcinoma of the bone, carcinoma of thethyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma,gastrointestinal cancer, colon carcinoma, colorectal adenoma, a tumor ofthe neck and/or head, an epidermal hyperproliferation, psoriasis,prostate hyperplasia, a neoplasia, a neoplasia of epithelial character,adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, largecell carcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkinslymphoma, Non-Hodgkins lymphoma, mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, IL-1 driven disorders, MyD88 driven disorders, ABC diffuselarge B-cell lymphoma (DLBCL), Waldenström's macroglobulinemia, primarycutaneous T-cell lymphoma, chronic lymphocytic leukemia, smolderingmultiple myeloma, indolent multiple myeloma, hematological malignancies,leukemia, acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chroniclymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primaryeffusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocyticleukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma,myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera,Kaposi's sarcoma, Waldenström's macroglobulinemia (WM), splenic marginalzone lymphoma, multiple myeloma, plasmacytoma, intravascular largeB-cell lymphoma, drug resistant malignancies, JAK inhibitor-resistantmalignancies, ibrutinib-resistant malignancies, ibrutinib resistanthematological malignancies, ibrutinib-resistant CLL, oribrutinib-resistant Waldenström's macroglobulinemia.

In one embodiment, the presently disclosed compounds can be used to slowthe onset of the consequences of aging. For example, the presentcompounds reduce the heightened chronic inflammation associated withadvanced age (“inflammaging”). Myriad symptoms and conditions areassociated with inflammaging, by way of example, such conditions thatcan be treated with the present compounds include, neurodegenerativedisorders, such as Parkinson's and Alzheimer's, hematopoietic neoplasmsand myeloproliferative disorders. Additional conditions that can betreated or ameliorated by the present compounds include those describedby Franceschi C, Campisi J. Chronic inflammation (inflammaging) and itspotential contribution to age-associated diseases. J. Gerontol A BiolSci Med Sci. 2014; 69 Suppl 1: S4-S9. In another aspect, the presentcompounds can be used to reduce aging effects on the reproductivesystem. For example, necroptosis induced by RIP1 signaling has beenimplicated in the aging of reproductive organs by Li et al. eLife 2017;6:e27692 and Chaudhary et al. Journal of Biomedical Science (2019)26:11, thus the present compounds could be used to treat symptoms ofassociated with aging, such as reduced testosterone levels, reducedfertility and prostate hyperplasia.

For particular embodiments, at least one compound, or a compositioncomprising at least one compound, according to the present invention isadministered to a subject having, or potentially developing, atopicdermatitis. In another particular embodiment, at least one compound, ora composition comprising at least one compound, according to the presentinvention is administered to a subject having, or potentiallydeveloping, rheumatoid arthritis. In another particular embodiment, atleast one compound, or a composition comprising at least one compound,according to the present invention is administered to a subject having,or potentially developing, ankylosing spondylitis. In another particularembodiment, at least one compound, or a composition comprising at leastone compound, according to the present invention is administered to asubject having, or potentially developing, myelodysplastic syndrome,such as a subject having myelofibrosis or polycythemia vera.

Examples of allergic disorders that may be treated using the disclosedcompound, combinations of disclosed compounds, or pharmaceuticalcompositions thereof, include, but are not limited to, asthma (e.g.atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma,non-atopic asthma, bronchial asthma, non-allergic asthma, essentialasthma, true asthma, intrinsic asthma caused by pathophysiologicdisturbances, essential asthma of unknown or unapparent cause,emphysematous asthma, exercise-induced asthma, emotion-induced asthma,extrinsic asthma caused by environmental factors, cold air inducedasthma, occupational asthma, infective asthma caused by or associatedwith bacterial, fungal, protozoal, or viral infection, incipient asthma,wheezy infant syndrome, bronchiolitis, cough variant asthma ordrug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA),allergic rhinitis, perennial allergic rhinitis, perennial rhinitis,vasomotor rhinitis, post-nasal drip, purulent or non-purulent sinusitis,acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoidsinusitis.

Rheumatoid arthritis is another example of a disorder that can betreated with the present compounds. Rheumatoid arthritis (RA) typicallyresults in swelling, pain, loss of motion and tenderness of targetjoints throughout the body. RA is characterized by chronically inflamedsynovium that is densely crowded with lymphocytes. The synovialmembrane, which is typically one cell layer thick, becomes intenselycellular and assumes a form similar to lymphoid tissue, includingdendritic cells, T-, B- and NK cells, macrophages and clusters of plasmacells. This process, as well as a plethora of immunopathologicalmechanisms including the formation of antigen-immunoglobulin complexes,eventually result in destruction of the integrity of the joint,resulting in deformity, permanent loss of function and/or bone erosionat or near the joint. The disclosed compound, combinations of disclosedcompounds, or pharmaceutical compositions thereof, may be used to treat,ameliorate or prevent any one, several or all of these symptoms of RA.Thus, in the context of RA, the compounds are considered to providetherapeutic benefit when a reduction or amelioration of any of thesymptoms commonly associated with RA is achieved, regardless of whetherthe treatment results in a concomitant treatment of the underlying RAand/or a reduction in the amount of circulating rheumatoid factor(“RF”).

The American College of Rheumatology (ACR) has developed criteria fordefining improvement and clinical remission in RA. Once such parameter,the ACR20 (ACR criteria for 20% clinical improvement), requires a 20%improvement in the tender and swollen joint count, as well as a 20%improvement in 3 of the following 5 parameters: patient's globalassessment, physician's global assessment, patient's assessment of pain,degree of disability, and level of acute phase reactant. These criteriahave been expanded for 50% and 70% improvement in ACR50 and ACR70,respectively. Other criteria include Paulu's criteria and radiographicprogression (e.g. Sharp score).

In some embodiments, therapeutic benefit in patients suffering from RAis achieved when the patient exhibits an ACR20. In specific embodiments,ACR improvements of ACRC50 or even ACR70 may be achieved.

B. Formulations and Administration

Pharmaceutical compositions comprising one or more active compounds ofthe disclosure may be manufactured by any suitable method, such asmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilization processes. Thepharmaceutical compositions may be formulated using one or morephysiologically acceptable excipients (e.g., diluents, carriers, orauxiliaries), one or more adjuvants, or combinations thereof to providepreparations which can be used pharmaceutically.

The active compound(s) may be formulated in the pharmaceuticalcompositions per se, or in the form of a pharmaceutically acceptablesalt, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, anisotope, or a prodrug thereof. Typically, such salts are more soluble inaqueous solutions than the corresponding free acids and bases, but saltshaving lower solubility than the corresponding free acids and bases mayalso be formed.

Pharmaceutical compositions of the disclosure may take a form suitablefor virtually any mode of administration, including, for example,topical, ocular, oral, buccal, systemic, nasal, injection, such as i.v.or i.p., transdermal, rectal, vaginal, etc., or a form suitable foradministration by inhalation or insufflation.

For topical administration, the active compound(s), pharmaceuticallyacceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate,isotope, or prodrug may be formulated as solutions, gels, ointments,creams, suspensions, etc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thepharmaceutical compositions may also contain formulating agents, such assuspending, stabilizing and/or dispersing agent. The formulations forinjection may be presented in unit dosage form, e.g., in ampules or inmultidose containers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile, pyrogen-free water, buffer, dextrose solution, etc., beforeuse. To this end, the active compound(s) maybe dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients, such as:binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); and/or wetting agents (e.g., sodiumlauryl sulfate). The tablets may be coated by methods well known in theart with, for example, sugars, films or enteric coatings.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable excipients such as:suspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, Cremophore™ or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound, as is well known.

For buccal administration, the pharmaceutical compositions may take theform of tablets or lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)may be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases, such as cocoabutter or other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s), pharmaceutically acceptable salt,stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrugcan be conveniently delivered in the form of an aerosol spray frompressurized packs or a nebulizer with the use of a suitable propellant,e.g.) dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound (0.5 20 mg/ml);benzalkonium chloride (0.1 0.2 mg/mL); polysorbate 80 (TWEEN® 80; 0.5 5mg/ml); carboxymethylcellulose sodium or microcrystalline cellulose (115 mg/ml); phenylethanol (1 4 mg/ml); and dextrose (20 50 mg/ml). The pHof the final suspension can be adjusted to range from about pH 5 to pH7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension suitable foradministration of the compounds via inhalation contains 20 mg/mL of thedisclosed compound(s), 1% (v/v) polysorbate 80 (TWEEN® 80), 50 mMcitrate and/or 0.9% sodium chloride.

For ocular administration, the active compound(s) may be formulated as asolution, emulsion, suspension, etc. suitable for administration to theeye. A variety of vehicles suitable for administering compounds to theeye are known in the art. Specific non-limiting examples are describedin U.S. Pat. Nos. 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445;5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851,which are incorporated herein by reference.

For prolonged delivery, the active compound(s) can be formulated as adepot preparation for administration by implantation or intramuscularinjection. The active ingredient maybe formulated with suitablepolymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptionmay be used. To this end, permeation enhancers may be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. Nos. 5,407,713;5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189;5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which areincorporated herein by reference.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver active compound(s). Certain organicsolvents, such as dimethylsulfoxide (DMSO), may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

Several approaches exist for transporting molecules across the bloodbrain barrier. These include, but are not limited to physical methods,lipid-based methods, and receptor and channel-based methods. Physicalmethods of transporting a compound across the blood-brain barrierinclude, but are not limited to, circumventing the blood-brain barrierentirely, and/or creating openings in the blood-brain barrier.Circumvention methods include, but are not limited to, direct injection(e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002),interstitial infusion/convection enhanced delivery (Bobo et al., Proc.Natl. Acad. Sci. U.S.A. 91:2076-2080, 1994), and implanting a deliverydevice in the brain (see, e.g., Gill et al., Nature Med. 9:589-595,2003. Openings in the blood-brain barrier include, but are not limitedto, ultrasound, osmotic pressure (e.g., by administration of hypertonicmannitol and permeabilization by, e.g., bradykinin or permeabilizer A-7(see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and5,686,416). Compounds also may be encapsulated in liposomes that arecoupled to antibody binding fragments that bind to receptors on thevascular endothelium of the blood-brain barrier.

For certain embodiments, the compounds can be administered continuouslyby infusion into the fluid reservoirs of the CNS or by bolus injection.Compounds can be administered using an indwelling catheter and acontinuous administration means such as a pump, or by Implantation of asustained-release vehicle. For example, the compounds may be injectedthrough chronically implanted cannulas or chronically infused with thehelp of osmotic minipumps. Subcutaneous pumps can deliver compounds tothe cerebral ventricles.

C. Dosages

The disclosed compound, pharmaceutical compositions, or combinations ofdisclosed compounds will generally be used in an amount effective toachieve the intended result, for example, in an amount effective toinhibit a RIP1 kinase and/or to treat, prevent or ameliorate aparticular condition. The disclosed compound(s), or pharmaceuticalcompositions thereof, can be administered therapeutically to achievetherapeutic benefit or prophylactically to achieve a prophylacticbenefit. Therapeutic benefit means eradication or amelioration of theunderlying disorder being treated and/or eradication or amelioration ofone or more of the symptoms associated with the underlying disorder suchthat the patient reports an improvement in feeling or condition,notwithstanding that the patient may still be afflicted with theunderlying disorder. For example, administration of a compound to apatient suffering from an allergy provides therapeutic benefit not onlywhen the underlying allergic response is eradicated or ameliorated, butalso when the patient reports a decrease in the severity or duration ofthe symptoms associated with the allergy following exposure to theallergen. As another example, therapeutic benefit in the context ofasthma includes an improvement in respiration following the onset of anasthmatic attack or a reduction in the frequency or severity ofasthmatic episodes. Therapeutic benefit also includes halting or slowingthe progression of the disease, regardless of whether improvement isrealized.

As known by those of ordinary skill in the art, the preferred dosage ofdisclosed compounds may depend on various factors, including the age,weight, general health, and severity of the condition of the patient orsubject being treated. Dosage also may need to be tailored to the sex ofthe individual and/or the lung capacity of the individual, whenadministered by inhalation. Dosage may also be tailored to individualssuffering from more than one condition or those individuals who haveadditional conditions that affect lung capacity and the ability tobreathe normally, for example, emphysema, bronchitis, pneumonia,respiratory distress syndrome, chronic obstructive pulmonary disease,and respiratory infections. Dosage, and frequency of administration ofthe disclosed compound(s) or pharmaceutical compositions thereof, willalso depend on whether the disclosed compound(s) are formulated fortreatment of acute episodes of a condition or for the prophylactictreatment of a disorder. A person of ordinary skill in the art will beable to determine the optimal dose for a particular individual.

For prophylactic administration, the disclosed compound, combinations ofdisclosed compounds, or pharmaceutical compositions thereof, can beadministered to a patient or subject at risk of developing one of thepreviously described conditions. For example, if it is unknown whether apatient or subject is allergic to a particular drug, the disclosedcompound, combinations of disclosed compounds, or pharmaceuticalcompositions thereof, can be administered prior to administration of thedrug to avoid or ameliorate an allergic response to the drug.Alternatively, prophylactic administration can be used to avoid orameliorate the onset of symptoms in a patient diagnosed with theunderlying disorder. For example, a disclosed compound(s), orpharmaceutical composition thereof, can be administered to an allergysufferer prior to expected exposure to the allergen. A disclosedcompound, combinations of disclosed compounds, or pharmaceuticalcompositions thereof, can also be administered prophylactically tohealthy individuals who are repeatedly exposed to agents known to one ofthe above-described maladies to prevent the onset of the disorder. Forexample, a disclosed compound, combinations of disclosed compounds, orpharmaceutical compositions thereof, can be administered to a healthyindividual who is repeatedly exposed to an allergen known to induceallergies, such as latex, in an effort to prevent the individual fromdeveloping an allergy. Alternatively, a disclosed compound, combinationsof disclosed compounds, or pharmaceutical compositions thereof, can beadministered to a patient suffering from asthma prior to partaking inactivities which trigger asthma attacks to lessen the severity of, oravoid altogether, an asthmatic episode.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in subjects can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ or EC₅₀ of the particular compound asmeasured in an in vitro assay. Dosages can be calculated to achieve suchcirculating blood or serum concentrations taking into account thebioavailability of the particular compound. Fingl & Woodbury, “GeneralPrinciples,” In: Goodman and Gilman's The Pharmaceutical Basis ofTherapeutics, Chapter 1, pages 1-46, Pergamon Press, and the referencescited therein, provide additional guidance concerning effective dosages.

In some embodiments, the disclosed compounds have an EC₅₀ from greaterthan 0 to 20 μM, such as from greater than 0 to 10 μM, from greater than0 to 5 μM, from greater than 0 to 1 μM, from greater than 0 to 0.5 μM,from greater than 0 to 0.1 μM, or from greater than 0 to 0.05 μM.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, (1995) Allergy 50(21Supp1):6-9,discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., (2000), Arzneimittelforschung50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7.Persons of ordinary skill in the art can adapt such information todetermine dosages suitable for human administration.

In some embodiments, assays suitable for determining RIP1 activity canbe used. Such assay methods can be used to evaluate the efficacy ofcompound embodiments disclosed herein and/or that can be used todetermine amounts/dosages of the compound embodiments that can provide adesired efficacy. In some embodiments, the assay can be an ADP-Glo™assay that assesses the ability of a compound embodiment to inhibitRIP1. In other embodiments, whole cell assays using mouse and/or humancells, such as U937 and/or L929 cell necroptosis assays, can beperformed to determine safe and effective doses of compounds that can beused in human in vivo studies. Using these whole cell assays, thecompound's activity against human and/or murine RIP1 can be assessed inan in vitro context, which then allows a person of ordinary skill in theart to determine safe and effective dosages for in vivo use. Yet anotherassay that can be used to evaluate the activity of compound embodimentsdescribed herein to treat a disease or condition involving RIP1 is anacute hypothermia mouse model, which assesses the compound's ability toinhibit TNF-alpha induced hypothermia. Each of these assays, and variousresults from using these assays, are described in detail in the Examplessection of the present disclosure.

Dosage amounts of disclosed compounds will typically be in the range offrom greater than 0 mg/kg/day, such as 0.0001 mg/kg/day or 0.001mg/kg/day or 0.01 mg/kg/day, up to at least about 100 mg/kg/day. Moretypically, the dosage (or effective amount) may range from about 0.0025mg/kg to about 1 mg/kg administered at least once per day, such as from0.01 mg/kg to about 0.5 mg/kg or from about 0.05 mg/kg to about 0.15mg/kg. The total daily dosage typically ranges from about 0.1 mg/kg toabout 5 mg/kg or to about 20 mg/kg per day, such as from 0.5 mg/kg toabout 10 mg/kg per day or from about 0.7 mg/kg per day to about 2.5mg/kg/day. Dosage amounts can be higher or lower depending upon, amongother factors, the activity of the disclosed compound, itsbioavailability, the mode of administration, and various factorsdiscussed above.

Dosage amount and dosage interval can be adjusted for individuals toprovide plasma levels of the disclosed compound that are sufficient tomaintain therapeutic or prophylactic effect. For example, the compoundscan be administered once per day, multiple times per day, once per week,multiple times per week (e.g., every other day), one per month, multipletimes per month, or once per year, depending upon, amongst other things,the mode of administration, the specific indication being treated, andthe judgment of the prescribing physician. Persons of ordinary skill inthe art will be able to optimize effective local dosages without undueexperimentation.

Pharmaceutical compositions comprising one or more of the disclosedcompounds typically comprise from greater than 0 up to 99% of thedisclosed compound, or compounds, and/or other therapeutic agent bytotal weight percent. More typically, pharmaceutical compositionscomprising one or more of the disclosed compounds comprise from about 1to about 20 total weight percent of the disclosed compound and othertherapeutic agent, and from about 80 to about 99 weight percent of apharmaceutically acceptable excipient. In some embodiments, thepharmaceutical composition can further comprise an adjuvant.

Preferably, the disclosed compound, combinations of disclosed compounds,or pharmaceutical compositions thereof, will provide therapeutic orprophylactic benefit without causing substantial toxicity. Toxicity ofthe disclosed compound can be determined using standard pharmaceuticalprocedures. The dose ratio between toxic and therapeutic (orprophylactic) effect is the therapeutic index. Disclosed compounds thatexhibit high therapeutic indices are preferred.

V. Examples Example 1

Compounds of the present disclosure can be made using a suitablestarting compound, such as compound 200 or compound 206, illustrated inthe schemes above. A representative method for making compound 200 isillustrated in Scheme 6A and a representative method for making compound206 is illustrated in Scheme 6B.

Spectral characterization for3-(S)—N-trityl-amino-7-bromo-5-methyl-4-oxobenzoxazapine (200): ¹H nmr(400 MHz, CDCl₃) δ 7.41-7.38 (6H, m, 6H of C(C₆H₅)3), 7.25-7.15 (10H, m,oxobenzoxazapineH-8, 9H of C(C₆H₅)₃), 7.00 (1H, d, J 2.5 Hz,oxobenzoxazapineH-6), 6.91 (1H, d, J 8.5 Hz, oxobenzoxazapineH-9), 4.50(1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.37 (1H, dd, J11.5, 10.0 Hz, 1H of oxobenzoxazapineH-2), 3.53 (1H, dd, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 3.30 (1H, br s, NH), 2.87 (3H, s, NCH₃).

Characterization data and particular methods of making representativecompounds disclosed herein are provided below.

Example 2

Synthesis of(S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one:A mixture of the bromooxazepine (0.210 g, 0.410 mmol, 1.0 eq) potassiumcarbonate (0.566 g, 4.101 mmol, 10.0 eq) and copper(I) iodide (0.008 g,0.041 mmol, 0.1 eq) in dimethylformamide (3.0 mL) was degassed bybubbling argon through for five minutes. 2-Methyl-2-hydroxybut-3-yne(0.052 g, 0.060 mL, 0.615 mmol, 1.5 eq) andtetrakis(triphenylphosphine)palladium (0.024 g, 0.021 mmol, 0.05 eq)were added and the reaction sealed before heating in the microwave to120° C. for 1 hour. The reaction was partitioned between EtOAc (80 mL)and water (80 mL). The organics were washed with brine (80 mL), water(80 mL) and brine (80 mL), dried (Na₂SO₄) and concentrated under reducedpressure. MPLC (1080% EtOAc-hexane) yielded the starting material (0.091g) and the title compound (0.079 g) as a colorless oil; ¹H nmr (400 MHz,CDCl₃) δ 7.40-7.38 (6H, m, 6H of C(C₆H₅)₃), 7.24-7.7.14 (9H, m, 9H ofC(C₆H₅)₃), 7.13 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazepineH-8), 6.96 (1H,d, J 8.0 Hz, oxobenzoxazepineH-9), 6.95 (1H, d, J 2.5 Hz,oxobenzoxazapineH-6), 4.48 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazepineH-2), 4.37 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazepineH-2), 3.55 (1H, dd, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 2.78 (3H, s, NCH₃), 1.62 (6H, s, C(CH₃)₂); m/z:555 [M+K]⁺, 243 [C(C₆H₅)₃]⁺.

Deprotection of the Trityl Group: To a solution of the trityl protectedamine (0.079 g, 0.153 g, 1.0 eq) in dioxane (2.0 mL) was added asolution of hydrogen chloride (0.15 mL of a 4M solution in dioxane,0.614 mmol, 4.0 eq). The reaction was stirred at room temperature for 6hours before concentrating to dryness to obtain a white solid, which wasused without purification; m/z: 275 [M+H]⁺.

Example 3

Synthesis of ethyl(S,E)-3-(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)acrylate:To a suspension of tert-butyl(S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate(0.500 g, 1.35 mmol, 1.0 eq) in dimethylformamide (8 mL) was degassed bybubbling argon through for five minutes. Ethyl acrylate (0.270 g, 0.29mL, 2.70 mmol, 2.0 eq) and triethylamine (0.272 g, 0.37 mL, 2.0 eq) wereadded followed by tetrakis(triphenylphosphine (0.156 g, 0.14 mmol, 0.1eq). The reaction was sealed and heated in the microwave to 100° C. for1 hour and 120° C. for 1 hour. The reaction was partitioned betweenEtOAc (100 mL) and water (100 mL). The organics were washed with brine(70 mL), water (100 mL) and brine (70 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. Column chromatography (1040%EtOAc-hexane) yielded the title compound (0.250 g, %) as a yellow foam;¹H nmr (400 MHz, CDCl₃) δ 7.62 (1H, d, J 16.0 Hz, ArCH═CHCO), 7.35 (1H,dd, J 8.0, 2.0 Hz, oxobenzoxazepineH-8), 7.33 (1H, d, J 2.0 Hz,oxobenzoxazepineH-6), 7.14 (1H, d, J 8.0 Hz, oxobenzoxazepineH-9), 6.37(1H, d, J 16.0 Hz, ArCH═CHCO), 5.49 (1H, d, J 7.0 Hz, NH), 4.65 (1H, dt,J 11.0, 7.0 Hz, oxobenzoxazepineH-3), 4.57 (1H, dd, J 9.5, 7.0 Hz, 1H ofoxobenzoxazepineH-2), 4.27 (2H, q, J 7.0 Hz, OCH ₂CH₃), 4.19 (1H, dd, J11.0, 9.5 Hz, 1H of oxobenzoxazepineH-2), 3.41 (3H, s, NCH₃), 1.39 (9H,s, C(CH₃)₃), 1.34 (3H, t, J 7.0 Hz, OCH₂CH ₃); m/z: 291 [M+H—CO₂—C₄H₈]⁺.

Synthesis of ethyl(S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate:A solution of the α,β-unsaturated ester (0.25 g, 0.64 mmol, 1.0 eq) inethyl acetate (20 mL) was added palladium on carbon (0.23 g). Thereaction was purged with hydrogen and stirred under an atmosphere ofhydrogen for 14 hours. The reaction was purged with nitrogen andfiltered through Celite®, eluting with ethyl acetate (2×20 mL). Thefiltrate was concentrated under reduced pressure; ¹H nmr (400 MHz,CDCl₃) δ 7.04-6.82 (3H, m, oxobenzoxazepineH-6, H-8, H-9), 5.50 (1H, d,J 7.5 Hz, NH), 4.61 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazepineH-3), 4.52(1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazepineH-2), 4.14-4.07 (1H, m, 1Hof oxobenzoxazepineH-2), 4.12 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.36 (3H, s,NCH₃), 2.91 (2H, t, J 7.5 Hz, 2H of ArCH₂CH₂CO), 2.59 (2H, t, J 7.5 Hz,2H of ArCH₂CH₂CO), 1.37 (9H, s, C(CH₃)₃), 1.23 (3H, t, J 7.0 Hz,OCH₂CH₃); m/z: 337 [M+H—C₄H₈]⁺, 293 [M+H—CO₂—C₄H₈]⁺. The crude materialwas dissolved in dichloromethane (10 mL). Hydrogen chloride (0.80 mL ofa 4M solution in dioxane, 3.21 mmol, 5.0 eq). The reaction was stirredat room temperature for 14 hours before adding further hydrogen chloridesolution (0.8 mL, 5.0 eq). After stirring for a further 2 hours thereaction was concentrated under reduced pressure and dried under vacuumto obtain a brown solid. The crude material was used without furtherpurification; m/z: 293 [M+H]⁺.

Example 4

Synthesis of(S,E)-3-(5-methyl-4-oxo-3-(tritylamino)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)acrylamide:To a mixture of the bromooxobenzoxazapine (0.300 g, 0.586 mmol, 1.0 eq)and acrylamide (0.062 g, 0.879 mmol, 1.5 eq) was added dimethylformamide(5 mL) and the mixture degassed by bubbling argon through for fiveminutes. Triethylamine (0.178 g, 0.24 mL, 1.758 mmol, 3.0 eq) was addedfollowed by X-PhosPd G2 (0.046 g, 0.059 mmol, 0.1 eq) and the reactionsealed and heated to 120° C. in the microwave for 1 hour. The reactionwas partitioned between EtOAc (100 mL) and NaHCO₃ (100 mL). The organicswere washed with brine (80 mL), water (100 mL) and brine (80 mL) dried(Na₂SO₄) and concentrated under reduced pressure. MPLC (0→10%MeOH—CH₂Cl₂) yielded the title compound (0.267 g, 91%) as a pale yellowsolid; ¹H nmr (400 MHz, CDCl₃) δ 7.55 (1H, d, J 15.5 Hz, ArCH═CHCO),7.39-7.36 (7H, m, 6H of C(C₆H₅)₃, oxobenzoxazapineH-8), 7.25-7.13 (9H,m, 9H of C(C₆H₅)₃), 7.01 (1H, d, J 8.5 Hz, oxobenzoxazepineH-9), 6.97(1H, d, J 2.0 Hz, oxobenzoxazepineH-6), 6.39 (1H, d, J 15.5 Hz,ArCH═CHCO), 5.95 (2H, br s, NH₂), 4.51 (1H, dd, J 9.5, 7.0 Hz, 1H ofoxobenzoxazepineH-2), 4.39 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazepineH-2), 3.54 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 3.31 (1H, d, J 8.5 Hz, NH), 2.94 (3H, s, NCH₃);m/z: 526 [M+Na]⁺, 243 [C(C₆H₅)₃]⁺.

Synthesis of(S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanamide:A solution of the α,β-unsaturated carboxamide (0.267 g, 0.532 mmol, 1.0eq) in ethyl acetate methanol (5:2, 7 mL) was purged with nitrogen andpalladium on carbon (0.100 g) added. The reaction was purged withhydrogen and stirred under an atmosphere of hydrogen for 2 hours. Thereaction was purged with nitrogen and filtered through celite, elutingwith EtOAc (30 mL). The filtrate was concentrated under reducedpressure. The residue was dissolved in dioxane (5 mL) and hydrogenchloride (0.66 mL of a 4M solution in dioxane, 2.659 mmol, 5.0 eq)added. The reaction was stirred at room temperature for 6 hours, a whitesolid formed. The reaction was concentrated to dryness and used withoutpurification; m/z: 265 [M+H]⁺.

Example 5

Formation of(S)-7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one:Dioxane (4 mL) and water (2 mL) were added to a mixture of thebromobenzoxazapine (0.270 g, 0.527 mmol, 1.0 eq),7-((trifluoro-2,49-boraneyl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine,potassium salt (0.180 g, 0.738 mmol, 1.4 eq) and caesium carbonate(0.515 g, 1.581 mmol, 3.0 eq). The reaction was degassed by bubblingargon through for ten minutes. X-PhosPd G2 (0.021 g, 0.026 mmol, 0.05eq) was added and the reaction sealed and heated in the microwave to140° C. for 45 minutes. The reaction was partitioned between EtOAc (80mL) and NaHCO₃ (80 mL). The organics were washed with brine (80 mL),dried (Na₂SO₄) and concentrated under reduced pressure. MPLC (0→10% MeOH[2M NH3]-CH₂Cl₂) yielded the title compound (0.255 g, %) as a yellowoil; ¹H nmr (400 MHz, CDCl₃) δ 7.88 (1H, s, triazoleH-3), 7.38-7.35 (6H,m, 6H of C(C₆H₅)₃), 7.21-7.11 (9H, m, 9H of C(C₆H₅)₃), 7.02 (1H, dd, J8.0, 2.0 Hz, oxobenzoxazapineH-8), 6.97 (1H, d, J 8.0 Hz,oxobenzoxazapineH-9), 6.87 (1H, d, J 2.0 Hz, oxobenzoxazapineH-6), 4.50(1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.36 (1H, dd, J11.5, 10.0 Hz, 1H of oxobenzoxazapineH-2), 4.16 (2H, t, J 5.5 Hz, 2H ofNCH₂CH₂N), 3.82 (2H, s, ArCH₂N or NCH₂CN), 3.69 (2H, s, ArCH₂N orNCH₂CN), 3.51 (1H, dd, J 11.5, 7.5 Hz, oxobenzoxazapineH-3), 2.91 (2H,t, J 5.5 Hz, 2H of ArCH₂CH₂N), 2.88 (3H, s, NCH₃); m/z: 593 [M+Na]⁺, 243[C(C₆H₅)₃]⁺.

Deprotection of the Trityl Group: To a solution of the trityl protectedamine (0.255 g, 0.447 mmol, 1.0 eq) in dioxazne (4.0 mL) was addedhydrogen chloride (0.56 mL of a 4M solution in dioxane, 2.237 mmol, 5.0eq). A white precipitate formed. The reaction was stirred at roomtemperature for 14 hours. The reaction was concentrated to dryness andused without purification; m/z: 329 [M+H]⁺.

(S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

¹H nmr (400 MHz, CDCl₃) δ 7.40-7.38 (6H, m, 3×2H of C₆H₅), 7.24-7.20(6H, m, 3×2H of C₆H₅), 7.18-7.12 (4H, m, 3×1H of C₆H₅, 1H ofoxbenzoxazapineH-6, H-8, H-9), 6.97-6.95 (2H, m, 2H ofoxobenzoxazapineH-6, H-8, H-9), 4.48 (1H, dd, J 9.5, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.37 (1H, dd, J 11.5, 9.5 Hz, 1H ofoxobenzoxazapineH-2), 3.55 (1H, dt, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 3.28 (1H, d, J 8.5 Hz, NH), 2.88 (3H, s, NCH₃),1.63 (6H, s, C(CH₃)₂OH); m/z: 561 [M−H+HCO₂H]⁻.

(S)-3-amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

¹H nmr (400 MHz, CDCl₃) δ 7.24 (1H, d, J 2.0 Hz, oxobenzoxazapineH-6),7.22 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8), 7.06 (1H, d, J 8.0Hz, oxobenzoxazapineH-9), 4.41 (1H, dd, J 10.0, 7.5 Hz, 1H ofoxobenzoxazapineH-2), 4.12 (1H, dd, J 11.5, 10.0 Hz, 1H ofoxobenzoxazapineH-2), 3.72 (1H, dd, J 11.5, 7.5 Hz,oxobenzoxazapineH-3); m/z: 275 [M+H]⁺ (found [M+H]⁺, 275.1390,C₁₅H₁₈N₂O₃ requires [M+H]⁺ 275.1404).

Example 6

This example concerns a method for making(S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamideaccording to Scheme 7.

Dimethylformamide (80 mL) was added to a mixture ofbromooxobenzoxazapine 1100 (8.36 g, 16.3 mmol, 1.0 eq) and copper iodide(0.31 g, 1.6 mmol, 0.1 eq). The mixture was degassed by bubbling argonthrough for five minutes. Triethylamine (11.4 mL, 81.6 mmol, 5.0 eq) wasadded followed by the hydroxyethynyloxetane 1102 (3.20 g, 32.7 mmol, 2.0eq) and tetrakis(triphenylphosphine)palladium (0.94 g, 0.8 mmol, 0.05eq). The resulting brown solution was heated to 80° C. for 4 hours. Thereaction was cooled and partitioned between EtOAc (200 mL) and water(200 mL). The organics were washed with brine (150 mL), water (200 mL)and brine (150 mL), dried (Na2SO4) and concentrated under reducedpressure. MPLC (10□70% EtOAc-hexane) yielded compound 1104 (6.18 g, 72%)as a yellow solid. 1H nmr (400 MHz, CD3Cl) δ 7.41-7.39 (6H, m, 6H ofC(C6H5)3), 7.25-7.15 (10H, m, 9H of C(C6H5)3, oxobenzoxazapineH-8),7.00-6.98 (2H, m, oxobenzoxazapineH-6, H-9), 4.94 (2H, d, J 7.0 Hz, 2Hof oxetaneH-2, H-4), 4.80 (2H, d, J 7.5 Hz, 2H of oxetaneH-2, H-4), 4.50(1H, dd, J 10.0, 7.0 Hz, 1H of oxobenzoxazapineH-2), 4.39 (1H, dd, J11.5, 10.0 Hz, 1H of oxobenzoxazapineH-2), 3.59-3.52 (1H, m,oxobenzoxazapineH-3), 3.29 (1H, d, J 9.0 Hz, NH), 2.89 (3H, s, NCH3).

Formic acid (50 mL) was added to the trityl protected amine 1104 (7.49g, 14.1 mmol, 1 eq) and the mixture stirred at room temperature for 4hours. Water (50 mL) was added and the reaction stirred at roomtemperature for 15 hours. The reaction was concentrated to remove someof the formic acid before diluting with water (100 mL). The organicswere extracted with EtOAc (50 mL) and set aside. The aqueous phase wasneutralized by the addition of NaOH (5M, portionwise to approximately 40mL). The organics were extracted with EtOAc (4×150 mL). The combinedneutralized organics were dried (Na2SO4) and concentrated under reducedpressure to obtain(S)-3-amino-74(3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one1106 (3.78 g, 93%) as a yellow solid which was used without furtherpurification. 1H nmr (400 MHz, D6-DMSO) δ 7.51 (1H, d, J 2.0 Hz,oxobenzoxazapineH-6), 7.29 (1H, dd, J 8.0, 2.0 Hz, oxobenzoxazapineH-8),7.14 (1H, d, J 8.0 Hz, oxobenoxazapineH-9), 4.74 (2H, d, J 7.0 Hz, 2H ofoxetaneH-2, H-4), 4.58 (2H, d, J 7.0 Hz, 2H of oxetaneH-2, H-4), 4.25(1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.01 (1H, dd, J11.5, 10.0 Hz, 1H of oxobenzoxazapineH-2), 3.59 (1H, dd, J 11.5, 7.5 Hz,oxobenzoxazapineH-3), 3.28 (3H, s, NCH3); 13C nmr (100 MHz, D6-DMSO) δ173.7, 150.7, 137.7, 130.2, 126.2, 126.6, 123.3, 119.1, 90.9, 84.5,83.7, 80.3, 66.3, 51.1, 35.1; m/z: 289 [M+H]⁺.

A solution of the aminooxobenzoxazapine 1106 (3.78 g, 13.13 mmol, 1.0eq) in dimethylformamide (70 mL) was degassed by bubbling nitrogenthrough for five minutes. 4-Phenoxypyridine-2-carboxylic acidhydrochloride 1108 (3.30 g, 13.13 mmol, 1.0 eq) was added and thesolution cooled to 0° C. before adding diisopropylethylamine (5.7 mL,32.81 mmol, 2.5 eq). HATU (5.49 g, 14.44 mmol, 1.1 eq) was addedportionwise and the reaction stirred at 0° C. for 1 hour and roomtemperature for 15 hours. The reaction was poured into ice-water (500mL) forming a precipitate, which after stirring for 15 minutes wasisolated by filtration. The filtrate was extracted with EtOAc (150 mL).The organic extracts were washed with brine (100 mL), water (150 mL) andbrine (100 mL), combined with the isolated precipitate, dried (Na2SO4)and concentrated under reduced pressure. MPLC (3070% EtOAc-hexane)yielded(S)—N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamideI-110 (5.20 g, 82%) as a white foam. IR (film) v 3357, 2941, 2875, 1662,1582, 1501, 1488, 1469, 1388, 1360, 1291, 1214, 1192, 1020, 979, 838,730 cm-1; 1H nmr (400 MHz, CDCl3) δ 8.86 (1H, d, J 7.5 Hz, NH), 8.44(1H, d, J 5.5 Hz, pyH-6), 7.61 (1H, d, J 2.5 Hz, pyH-3), 7.44-7.40 (2H,m, 2H of C6H5), 7.32-7.29 (2H, m, 2H of C6H5 or oxobenzoxazapineH-6,H-8), 7.27-7.23 (1H, m, 1H of C6H5 or oxobenzoxazapineH-6, H-8), 7.15(1H, d, J 9.0 Hz, oxobenzoxazapineH-9), 7.08-7.06 (2H, m, 2H of C6H5 oroxobenzoxazapineH-6, H-8), 6.50 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 5.04(1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.93 (2H, dd, J 4.0, 0.5Hz, oxetaneH-2, H-4), 4.79 (2H, dt, J 6.5, 1.0 Hz, oxetane H-2, H-4),4.71 (1H, dd, J 9.5, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.32 (1H, dd, J11.0, 9.5 Hz, 1H of oxobenzoxazapineH-2), 3.42 (3H, s, NCH3); 13C nmr(100 MHz, CDCl3) δ 168.9, 166.1, 163.7, 153.7, 151.2, 150.5, 150.1,136.4, 130.9, 130.3, 126.5, 125.7, 123.3, 120.7, 119.3, 114.5, 110.7,88.6, 84.8, 84.5, 77.2, 67.4, 49.3, 35.4; m/z: 486 [M+H]+ (found [M+H]+,486.1651, C27H23N3O6 requires [M+H]+ 486.1660).

Synthesis of tert-butyl 3-ethynyl-3-hydroxyazetidine-1-carboxylate

A solution of (trimethylsilyl)acetylene 1302 (0.71 g, 1.00 mL, 6.28mmol, 1.1 eq) in tetrahydrofuran (30 mL) was cooled to −78° C. andbutyllithium (2.51 mL of a 2.5M solution in hexane, 6.28 mmol, 1.1 eq)was added dropwise. The reaction was stirred at −78° C. for 1 hourbefore adding Boc-azetidinone 1300 (0.98 g, 5.71 mmol, 1.0 eq). Thereaction was stirred between −78° C. and room temperature for 20 hoursbefore quenching by the addition of NH₄Cl (20 mL). The reaction waspartitioned between EtOAc (100 mL) and NH₄Cl-water (1:1, 100 mL). Theorganics were washed with brine (100 mL), dried (Na₂SO₄) andconcentrated under reduced pressure.

The residue comprising 1304 was dissolved in tetrahydrofuran (30 mL) andcooled to 0° C. before adding tetrabutylammonium fluoride trihydrate(1.80 g, 5.71 mmol, 1.0 eq). The reaction was stirred at 0° C. for 3hours before adding NH₄Cl (20 mL). The reaction was partitioned betweenEtOAc (100 mL) and NH₄Cl-water (1:1, 100 mL). The organics were washedwith NH₄Cl (100 mL) and brine (100 mL), dried (Na₂SO₄) and concentratedunder reduced pressure to yield 1306 as a pale yellow oil. ¹H nmr (400MHz, CDCl₃) δ 4.20 (2H, dd, J 9.0, 1.0 Hz, 2H of azetidineH-2, H-4),4.02 (2H, dd, J 9.0, 1.0 Hz, 2H of azetidineH-2, H-4), 2.68 (1H, s,CCH), 1.44 (9H, s, C(CH₃)₃).

Example 7

This example provides a method for making embodiments of disclosedalkynyl substituted compounds according to the Scheme 8 below.

Nitrogen was bubbled through stirring solution of alyl/hetetoalylhalide1 (1 eq) and CuI (0.1-0.2 eq), Pd(PPh₃)₄ (0.05-0.1 eq) in dry DMF (3-4mL/mmol) for 3 minutes in a vial. Subsequently, NEt₃ (10 eq) was addedto the dark reaction solution followed by corresponding alkyne (1.5-3eq) in quick succession. Nitrogen was bubbled through the reactionmixture for 2 minutes, the vial capped, and the reaction mixture stirredat 70-75° C. for 5-6 hours. The dark reaction solution was concentratedto dryness after analyzing the reaction progression by LC/MS analysis.Crude residue was diluted with ice-water, sonicated and the slurry waswarmed to room temperature. The resulting grey/dark solid was collectedby filtration, suction dried, dissolved in THF (20 mL), filtered throughCelite®/silica gel pad, and the pad was washed with THF. Afterconcentration of the filtrate, the crude material was purified by flashchromatography to obtain alkynyl substituted analogs 2 (Yield: 25-69%).

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one(I-23)

¹H NMR (400 MHz, CDCl₃) δ 7.34-7.25 (m, 7H), 7.09 (d, J=8.2 Hz, 1H),5.89 (dd, J=11.7, 8.0 Hz, 1H), 5.39 (s, 2H), 4.63 (dd, J=11.8, 9.9 Hz,1H), 4.40 (dd, J=10.0, 8.0 Hz, 1H), 4.23 (dt, J=12.0, 5.2 Hz, 1H),3.60-3.43 (m, 1H), 3.37 (s, 3H), 3.04 (ddd, J=15.5, 10.4, 5.1 Hz, 1H),2.66 (ddd, J=15.6, 5.4, 4.4 Hz, 1H), 1.63 (s, 6H). ¹³C NMR (100 MHz,CDCl₃) δ 169.43, 160.87, 149.99, 142.32, 136.85, 135.21, 130.66, 128.89,128.35, 127.87, 126.64, 122.87, 120.70, 118.18, 94.60, 80.97, 74.87,65.78, 53.99, 51.26, 45.48, 35.72, 31.59, 31.58, 19.91. MS (ESI, m/e)Calculated 518.1721; Found 519.1 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-1

¹H NMR (400 MHz, DMSO-d₆) δ 7.47 (d, J=8.3 Hz, 1H), 7.38-7.29 (m, 4H),7.23 (d, J=1.9 Hz, 1H), 7.21-7.17 (m, 2H), 5.53 (dd, J=11.9, 7.9 Hz,1H), 5.43 (s, 2H), 4.84 (dd, J=12.0, 10.1 Hz, 1H), 4.38 (dd, J=10.1, 7.8Hz, 1H), 4.00 (dt, J=12.4, 6.2 Hz, 1H), 3.63 (ddd, J=12.9, 8.4, 4.9 Hz,1H), 3.29 (s, 3H), 2.85-2.74 (m, 1H), 2.68 (ddd, J=11.9, 8.4, 5.6 Hz,1H), 1.47 (s, 6H). MS (ESI, m/e) Calculated 518.1721; Found 519.1[M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-2

¹H NMR (400 MHz, DMSO-d₆) δ 7.45 (d, J=8.3 Hz, 1H), 7.38-7.26 (m, 4H),7.22-7.16 (m, 3H), 5.52 (dd, J=11.9, 7.8 Hz, 1H), 5.43 (s, 2H), 4.83(dd, J=12.0, 10.1 Hz, 1H), 4.37 (dd, J=10.0, 7.9 Hz, 1H), 4.00 (dt,J=12.2, 5.7 Hz, 1H), 3.62 (ddd, J=12.8, 8.4, 4.8 Hz, 1H), 3.28 (s, 3H),2.83-2.74 (m, 1H), 2.73-2.65 (m, 1H), 1.29 (s, 9H). MS (ESI, m/e)Calculated 516.1928; Found 517.1 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-74(1-hydroxycyclopentyl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(R938188)

¹H NMR (400 MHz, DMSO-d₆) δ 7.47 (d, J=8.4 Hz, 1H), 7.38-7.27 (m, 4H),7.23 (d, J=1.9 Hz, 1H), 7.21-7.17 (m, 2H), 5.53 (dd, J=11.9, 7.9 Hz,1H), 5.43 (s, 2H), 4.89-4.77 (m, 1H), 4.37 (dd, J=10.1, 7.8 Hz, 1H),4.00 (dt, J=12.4, 6.1 Hz, 1H), 3.63 (ddd, J=12.8, 8.4, 4.8 Hz, 1H), 3.29(s, 3H), 2.86-2.74 (m, 1H), 2.74-2.62 (m, 1H), 1.97-1.81 (m, 5H),1.81-1.61 (m, 2H). MS (ESI, m/e) Calculated 544.1877; Found 545.1[M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-4-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-4

¹H NMR (400 MHz, DMSO-d₆) δ 8.68-8.61 (m, 2H), 7.67-7.48 (m, 5H), 7.33(dt, J=14.2, 7.0 Hz, 3H), 7.23-7.16 (m, 2H), 5.56 (dd, J=11.9, 7.8 Hz,1H), 5.43 (s, 2H), 4.98-4.79 (m, 1H), 4.41 (dd, J=10.0, 7.8 Hz, 1H),4.08-3.96 (m, 1H), 3.64 (ddd, J=12.7, 8.3, 4.7 Hz, 1H), 2.81 (ddd,J=14.2, 8.4, 5.1 Hz, 1H), 2.75-2.66 (m, 1H). MS (ESI, m/e) Calculated537.1568; Found 538.0 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-3-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (d, J=2.1 Hz, 1H), 8.61 (dd, J=4.9, 1.6Hz, 1H), 8.00 (dt, J=7.9, 2.0 Hz, 1H), 7.63-7.43 (m, 4H), 7.40-7.26 (m,3H), 7.23-7.13 (m, 2H), 5.56 (dd, J=11.9, 7.8 Hz, 1H), 5.43 (s, 2H),4.93-4.83 (m, 1H), 4.41 (dd, J=10.1, 7.8 Hz, 1H), 4.01 (dt, J=12.4, 6.1Hz, 1H), 3.64 (ddd, J=12.8, 8.4, 4.7 Hz, 1H), 3.32 (s, 3H), 2.81 (ddd,J=13.9, 8.5, 5.1 Hz, 1H), 2.73-2.63 (m, 1H). MS (ESI, m/e) Calculated537.1568; Found 538.1 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-6

¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (d, J=4.6 Hz, 1H), 7.87 (td, J=7.7, 1.8Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.57 (d, J=1.5 Hz, 2H), 7.49 (s, 1H),7.44 (dd, J=7.7, 4.8 Hz, 1H), 7.39-7.26 (m, 3H), 7.22-7.16 (m, 2H), 5.56(dd, J=11.9, 7.8 Hz, 1H), 5.43 (s, 2H), 4.89 (dd, J=12.0, 10.1 Hz, 1H),4.42 (dd, J=10.1, 7.8 Hz, 1H), 4.01 (ddd, J=12.3, 7.3, 5.2 Hz, 1H), 3.65(ddd, J=12.8, 8.4, 4.9 Hz, 1H), 3.32 (s, 3H), 2.81 (ddd, J=14.0, 8.4,5.1 Hz, 1H), 2.69 (ddd, J=15.4, 7.0, 4.8 Hz, 1H). MS (ESI, m/e)Calculated 537.1568; Found 538.2 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-(tert-butoxy)prop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-7

¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (d, J=8.3 Hz, 1H), 7.41-7.26 (m, 5H),7.21-7.17 (m, 2H), 5.52 (dd, J=11.9, 7.8 Hz, 1H), 5.43 (s, 2H),4.91-4.79 (m, 1H), 4.37 (dd, J=10.0, 7.8 Hz, 1H), 4.30 (s, 2H), 4.00(dt, J=12.4, 6.0 Hz, 1H), 3.63 (ddd, J=12.9, 8.4, 4.8 Hz, 1H), 3.29 (s,3H), 2.80 (ddd, J=14.0, 8.4, 5.1 Hz, 1H), 2.68 (dt, J=15.8, 6.4 Hz, 1H),1.20 (s, 9H). MS (ESI, m/e) Calculated 546.2034; Found 547.2 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-8

¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (d, J=8.3 Hz, 1H), 7.42 (dd, J=8.3, 1.9Hz, 1H), 7.39-7.26 (m, 4H), 7.23-7.14 (m, 2H), 5.53 (dd, J=11.9, 7.8 Hz,1H), 5.43 (s, 2H), 4.86 (dd, J=11.9, 10.1 Hz, 1H), 4.76 (d, J=6.3 Hz,2H), 4.60 (d, J=6.4 Hz, 2H), 4.38 (dd, J=10.0, 7.8 Hz, 1H), 4.01 (ddd,J=12.4, 7.0, 5.0 Hz, 1H), 3.63 (ddd, J=12.9, 8.3, 4.8 Hz, 1H), 3.30 (s,3H), 2.80 (ddd, J=15.4, 8.4, 5.1 Hz, 1H), 2.68 (ddd, J=15.7, 7.0, 4.8Hz, 1H). MS (ESI, m/e) Calculated 532.1513; Found 533.0 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-9

¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (d, J=8.3 Hz, 1H), 7.41 (dd, J=8.5, 1.9Hz, 1H), 7.38-7.27 (m, 4H), 7.19 (d, J=7.4 Hz, 2H), 5.53 (dd, J=11.9,7.8 Hz, 1H), 5.43 (s, 2H), 4.90-4.77 (m, 1H), 4.38 (dd, J=10.1, 7.8 Hz,1H), 4.34 (s, 2H), 4.00 (dt, J=12.3, 6.1 Hz, 1H), 3.63 (ddd, J=12.8,8.5, 4.8 Hz, 1H), 3.34 (s, 3H), 3.29 (s, 3H), 2.80 (ddd, J=14.0, 8.4,5.1 Hz, 1H), 2.74-2.66 (m, 1H). MS (ESI, m/e) Calculated 504.1564; Found505.0 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-10

¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (d, J=8.3 Hz, 1H), 7.42-7.26 (m, 5H),7.21-7.17 (m, 2H), 5.53 (dd, J=11.9, 7.8 Hz, 1H), 5.43 (s, 2H),4.89-4.80 (m, 1H), 4.38 (dd, J=10.0, 7.8 Hz, 1H), 4.00 (dt, J=12.3, 6.1Hz, 1H), 3.63 (ddd, J=12.9, 8.4, 4.8 Hz, 1H), 3.32 (s, 3H), 3.29 (s,3H), 2.80 (ddd, J=13.8, 8.5, 5.1 Hz, 1H), 2.75-2.62 (m, 1H), 1.48 (d,J=0.8 Hz, 6H). MS (ESI, m/e) Calculated 532.1877; Found 533.1 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-11)

¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (d, J=8.3 Hz, 1H), 7.39-7.28 (m, 4H),7.25 (d, J=1.9 Hz, 1H), 7.24-7.21 (m, 2H), 5.50 (s, 2H), 5.05 (dd,J=12.2, 7.5 Hz, 1H), 4.93 (dd, J=12.2, 9.8 Hz, 1H), 4.84 (d, J=15.8 Hz,1H), 4.53-4.43 (m, 2H), 3.28 (s, 3H), 1.47 (s, 6H). MS (ESI, m/e)Calculated 504.1564; Found 527.0 [M+Na]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-12

¹H NMR (400 MHz, DMSO-d₆) δ 7.45 (d, J=8.3 Hz, 1H), 7.40-7.25 (m, 4H),7.22 (d, J=1.9 Hz, 1H), 7.21-7.17 (m, 2H), 5.52 (dd, J=11.9, 7.9 Hz,1H), 5.43 (s, 2H), 4.83 (dd, J=11.9, 10.1 Hz, 1H), 4.36 (dd, J=10.0, 7.8Hz, 1H), 4.06-3.95 (m, 1H), 3.62 (ddd, J=12.8, 8.5, 4.8 Hz, 1H), 3.35(s, 2H), 3.28 (s, 3H), 2.86-2.74 (m, 1H), 2.73-2.62 (m, 1H), 1.20 (s,6H). MS (ESI, m/e) Calculated 532.1877; Found 533.1 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-13

¹H NMR (400 MHz, DMSO-d₆) δ 8.96 (d, J=2.0 Hz, 1H), 8.29 (dd, J=8.2, 2.1Hz, 1H), 8.00 (dd, J=8.2, 0.9 Hz, 1H), 7.67-7.58 (m, 2H), 7.56 (d, J=1.7Hz, 1H), 7.41-7.29 (m, 3H), 7.27-7.20 (m, 2H), 5.51 (s, 2H), 5.10 (dd,J=12.1, 7.5 Hz, 1H), 4.98 (dd, J=12.2, 9.8 Hz, 1H), 4.84 (d, J=15.8 Hz,1H), 4.57-4.45 (m, 2H), 3.32 (s, 3H). MS (ESI, m/e) Calculated 591.1285;Found 592.1 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-14

¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 7.88(td, J=7.7, 1.8 Hz, 1H), 7.67 (dt, J=7.8, 1.1 Hz, 1H), 7.64-7.56 (m,2H), 7.51 (d, J=1.7 Hz, 1H), 7.44 (ddd, J=7.7, 4.9, 1.2 Hz, 1H),7.41-7.27 (m, 3H), 7.27-7.19 (m, 2H), 5.51 (s, 2H), 5.10 (dd, J=12.2,7.5 Hz, 1H), 4.98 (dd, J=12.2, 9.8 Hz, 1H), 4.84 (d, J=15.8 Hz, 1H),4.57-4.45 (m, 2H), 3.32 (s, 3H). MS (ESI, m/e) Calculated 523.1411;Found 524.0 [M+H]⁺.

(S)-6-((3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)ethynyl)picolinonitrile(I-15

¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (d, J=7.8 Hz, 1H), 8.07 (dd, J=7.8, 1.2Hz, 1H), 7.99 (dd, J=7.9, 1.2 Hz, 1H), 7.61 (dd, J=2.6, 1.2 Hz, 2H),7.55 (dd, J=1.7, 0.6 Hz, 1H), 7.38-7.27 (m, 3H), 7.22-7.16 (m, 2H), 5.56(dd, J=11.9, 7.8 Hz, 1H), 5.43 (s, 2H), 4.90 (dd, J=12.0, 10.1 Hz, 1H),4.42 (dd, J=10.1, 7.8 Hz, 1H), 4.01 (dt, J=12.3, 6.3 Hz, 1H), 3.65 (ddd,J=12.8, 8.4, 4.9 Hz, 1H), 3.33 (s, 3H), 2.81 (ddd, J=13.7, 8.3, 5.1 Hz,1H), 2.69 (ddd, J=15.3, 6.8, 4.7 Hz, 1H). MS (ESI, m/e) Calculated562.1520; Found 563.1 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-16)

¹H NMR (400 MHz, CD₂Cl₂) δ 7.41-7.22 (m, 5H), 7.09-6.97 (m, 1H), 6.30(d, J=7.2 Hz, 2H), 5.42 (s, 2H), 5.13 (dd, J=15.2, 0.6 Hz, 1H), 4.65(dd, J=12.1, 9.7 Hz, 1H), 4.34 (dd, J=9.7, 7.9 Hz, 1H), 4.21 (d, J=15.3Hz, 1H), 3.67 (d, J=0.8 Hz, 4H), 3.66-3.62 (m, 5H), 3.32 (s, 3H),1.92-1.77 (m, 4H). MS (ESI, m/e) Calculated 547.1986; Found 548.1[M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-17

MS (ESI, m/e) Calculated 561.2143; Found 562.2 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-18

MS (ESI, m/e) Calculated 537.1568.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-19

MS (ESI, m/e) Calculated 490.1408.

(3S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyrrolidin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-20

MS (ESI, m/e) Calculated 529.1881.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-74(6-methylpyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-21

MS (ESI, m/e) Calculated 551.1724.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-22

¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (td, J=7.9, 0.8 Hz, 1H), 7.98 (d, J=8.0Hz, 1H), 7.95 (dd, J=7.9, 0.9 Hz, 1H), 7.64 (dd, J=8.3, 1.9 Hz, 1H),7.60 (d, J=8.3 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.39-7.27 (m, 3H),7.23-7.16 (m, 2H), 5.56 (dd, J=11.9, 7.9 Hz, 1H), 5.43 (s, 2H),4.98-4.82 (m, 1H), 4.42 (dd, J=10.1, 7.8 Hz, 1H), 4.01 (p, J=6.1 Hz,1H), 3.65 (ddd, J=12.8, 8.4, 4.8 Hz, 1H), 3.33 (s, 3H), 2.81 (ddd,J=13.9, 8.3, 5.0 Hz, 1H), 2.69 (dt, J=15.4, 5.2 Hz, 1H). MS (ESI, m/e)Calculated 605.1442; Found 606.1 [M+H]⁺.

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one(I-23

¹H NMR (400 MHz, CDCl₃) δ 7.34-7.23 (m, 7H), 7.09 (d, J=8.2 Hz, 1H),5.89 (dd, J=11.7, 8.0 Hz, 1H), 5.39 (s, 2H), 4.63 (dd, J=11.8, 10.0 Hz,1H), 4.40 (dd, J=10.0, 8.0 Hz, 1H), 4.23 (dt, J=12.0, 5.2 Hz, 1H),3.59-3.45 (m, 1H), 3.37 (s, 3H), 3.04 (ddd, J=15.5, 10.4, 5.1 Hz, 1H),2.66 (ddd, J=15.6, 5.4, 4.4 Hz, 1H), 1.63 (s, 6H). ¹³C NMR (100 MHz,CDCl₃) δ 169.4, 160.9, 150.0, 142.3, 136.9, 135.2, 130.7, 128.9, 128.4,127.9, 126.6, 122.9, 120.7, 118.2, 94.6, 81.0, 74.9, 65.8, 54.0, 51.3,45.5, 35.7, 31.6, 31.6, 19.9. MS (ESI, m/e) Calculated 518.1721; Found519.1 [M+H]⁺.

Example 8

This example provides general methods for making the compounds describedherein. Exemplary compounds were prepared according to Scheme 9.

With reference to Scheme 9, isomers and analogs of intermediate 6-bromosubstituted compound 9-E can be prepared by, for example, beginning withan analog, such as the 7-bromo compound as is known to those of ordinaryskill in the art. Examples prepared according to the general methods ofScheme 9 include I-11, I-13, I-14 and I-16.

Additional examples were prepared according to the general methods ofScheme 10, including compounds I-1-I-10, I-12, I-15 and I-17-I-23. As inScheme 9, the position of R1 substituents can be varied by varying thestarting material 9-A, such as substituting the illustrated 6-bromocompound 9-A with, for example, the corresponding 7-bromo isomer. Adetailed procedure according to Scheme 10 and the methods disclosedherein is:

(S)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one(I-23)

To a solution of(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-bromo-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one1 (460 mg, 0.9 mmol) and 2-methylbut-3-yn-2-ol (0.2 mL, 174 mg 2.1 mmol)in anhydrous DMF (5 mL) were added Pd(PPh₃)₄(55 mg, 48 μmot), CuI (17mg, 89 μmol) and N,N-diisopropylethylamine (0.78 mL, 580 mg, 4.55 mmol).The sealed reaction vessel was then evacuated and filled with argon (3×)and heated at 80° C. for 3 hrs. The reaction mixture was then cooleddown to ambient temperature, concentrated under reduced pressure andpurified by column chromatography eluting with 0→100% ethyl acetatehexane. The desired fractions were combined and lyophilized to afford(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-oneas an off-white solid (380 mg, 82% yield).

Example 9

In this example, compounds of the disclosure were evaluated using abiochemical assay using the ADP-Glo™ technology.

ADP-Glo™ (Promega, Madison, Wis., USA) reagents were thawed at ambienttemperature. Kinase Detection Reagent was prepared by mixing kinasedetection buffer with the lyophilized kinase detection substrate.

A 500 ml stock volume of 5× Reaction Kinase Buffer was made by mixing10000 of 1M MgCl₂, 500 μl of 1M Tris-HCL pH7.4, 0.5 mg/ml (25 mg) ofBSA, and 3475 μl of distilled H₂O. A 3 ml 2× working stock volume ofReaction Kinase Buffer was made containing a final concentration of 100μM DTT and 4 mM MnCl₂.

Components of RIPK1 enzyme (Rigel Pharmaceuticals, South San Francisco,Calif., USA) were thawed on ice. Diluted RIPK1 was prepared in 1× KinaseReaction Buffer (diluted from 2× buffer) to 31 ng/well. A 166 μM workingstock ATP assay solution was prepared in 1× Kinase Reaction Buffer(diluted from 2× buffer).

Compounds were serially diluted in DMSO from 250 uM in 4-fold dilutionsthen diluted 1:5 in 2× Reaction Buffer in a 96 well plate. 1.0 ul ofdiluted compound was added to a 384 well plate in duplicate. 2 μl ofdiluted Active RIPK1 was added to 384 well plate (do not add tocolumn 1) add 2× r×n buffer to column 1. AKT (Anaspec, Fremont, Calif.,USA) at 150 nM was combined with ATP working stock at equal volume and 2ul/well were added to the 384 well plate. The final reaction volume was5.0 μl.

The plate was quickly centrifuged and the reaction was incubated at 30°C. for 30 minutes. Adding 5 μl of ADP-Glo™ terminated the reaction. Theplate was quickly centrifuged and the reaction was incubated at roomtemperature for 40 minutes. Kinase Detection Reagent was then added andincubated at room temperature for 30 minutes. The relative light unit(RLU) of kinase reaction was determined by luminescent (Luminescence0.1s) using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, Mass.,USA). IC₅₀ values obtained from this example are provided by Table 1.

TABLE 1 Compound RIPK1 ADP-Glo Kinase (IC₅₀) I-1 0.0396 I-2 0.3517 I-30.0839 I-4 0.1052 I-5 0.0488 I-6 0.0698 I-7 0.4265 I-8 0.0499 I-9 0.0728 I-10 0.1597  I-11 0.084  I-12 0.0621  I-13 0.7832  I-14 0.0814  I-150.2405  I-16 0.0604  I-17 0.0704  I-18 0.0956  I-19 0.0418  I-20 0.0633 I-21 0.1728  I-22 0.1541  I-23 0.0504

Example 10

In this example, U937 and L929 cells were exposed to compounds of thepresent disclosure and a cell necroptosis assay was conducted toevaluate the compounds' activity against human RIP1 and murine RIP1.

U937 and L929 cells were obtained from the American Type CultureCollection (Manassa, Va., USA). Both cells were maintained inlogarithmic growth phase in complete RPMI 1640 media (Sigma, ST Louis,Mo., USA) supplemented with 10% fetal bovine serum (Sigma, ST Louis,Mo., USA) at 37° C. with 5% CO₂. For necroptosis assay, L929 cells wereplated for 18h in 100 μL/well medium at 10K cells/well in Costar 96-wellblack clear-bottom plates (Fisher Scientific, Hampton, NH, USA); U937cells were plated on the day of the assay in 50 μL/well mediumcontaining 60 uM zVAD-fmk (Lonza, Basel, Switzerland) at 50K cells/well.Medium from L929 cells were removed from the 96-well plates and replacedwith 50 μL/well new medium containing 40 uM zVAD-fmk. Each compound ofthe present disclosure evaluated in this example was serially diluted inDMSO from 2.5 mM in 4-fold dilutions, and then diluted 1:125 in completemedium. 50 μL/well 2× of the compound was then added to the cells in theplates. The cells were pre-incubated with the compound for 1 hour at 37°C. with 5% CO₂ and before addition of 10 μL/well 11× TNFa (Peprotech,Rocky Hill, N.J., USA) to give a final concentration of 2 ng/mL forTNFa. The relative amount of necroptosis cells was determined byluminescent using a Wallac Victor2 Luminometer (PerkinElmer, Waltham,Mass., USA) and a CellTiter-Glo® Luminescent Cell Viability ReagentAssay (Promega, Madison, Wis., USA) added per manufacturer instructionsafter 18 hours of TNFa stimulation at 37° C. with 5% CO₂. Results fromthis example are summarized in Table 2. This example establishes thatembodiments of the compounds described herein have unexpectedly potentactivity against human RIP1 and murine RIP1, which allows theirassessment in in vivo mouse models of disease. These results are usefulin determining safe and effective doses for humans.

TABLE 2 L929-CTG-recovery, U937 Zvad TNF CTG L929, TNFa + zVAD Recovery,U937, TNFa + zVAD Compound (IC₅₀) (IC₅₀) I-1 0.0061 0.0022 I-2 0.03760.0391 I-3 0.0063 0.0028 I-4 0.0224 0.0161 I-5 0.0188 0.0106 I-6 0.02630.011 I-7 0.0264 0.0237 I-8 0.0096 0.006 I-9 0.0156 0.0032  I-10 0.00980.0032  I-11 0.3872 0.0046  I-12 0.0052 0.0026  I-13 6.126 0.0508  I-142.372 0.0262  I-15 0.0026 0.0031  I-16 0.1006 0.0234  I-17 0.0016 0.007 I-18 0.0017 0.0035  I-19 0.0027 0.0036  I-20 0.0151 0.0058  I-21 0.00180.0047  I-22 0.0388 0.0418  I-23 0.0016 0.0037 * ND indicates that noactivity was detected or that the inhibition curve showed artifacts.This value does not necessarily indicate an inactive compound, butindicates that the experiment failed to yield data for some reason. Byway of example, an insoluble compound or other experimental artifact canresult in a “ND” value.

Example 11

In this example, an acute hypothermia mouse model assay was used toevaluate the ability of compounds disclosed herein to inhibit TNF-alphainduced hypothermia.

Female C57BL/6 mice are randomly grouped and weighed on Day −1. On theday of the study (Day 0), mice are administered vehicle or test articleby oral gavage. Fifteen minutes after oral administration of testagents, each mouse is administered an intraperitoneal (IP) injection ofsolution containing recombinant human tumor necrosis factor alpha(TNF-a, 25.0 μg) and zVAD-FMK (200 μg). Body temperature is measured at0 hours (before IP injections) and every hour via rectal probetemperature measuring device. Three (3) hours after IP injections ofTNF-a and zVAD/FMK, mice are euthanized by CO₂ asphyxiation and blood iscollected via cardiac puncture. Serum and plasma are harvested fordetermination of cytokine and compound levels, respectively. Separategroups of mice (satellite mice) are included for the determination ofcompound levels in plasma at the time of administration ofTNFa/zVAD-FMK.

(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(WO 2014/125444), having a structure as illustrated below, was used as acomparative compound and was examined using a similar protocol asdescribed by WO 2014/125444. This comparative compound exhibited 93%inhibition at a dose of 30 mg/kg according to WO 2014/125444; however,in the inventors' hands, the compound inhibited only 70% at 30 mg/kg. Incomparison, compounds of the present disclosure achieved greaterinhibition at lower doses using the similar assay protocol describedabove.

Comparative Compound

Certain embodiments of the disclosure provide for compound, compounds orcompositions thereof to traverse the blood-brain barrier. Disclosedcompound and composition embodiments exhibit sufficient brainpenetration as potential therapeutics in neurological diseases. Brainpenetration may be assessed by evaluating free brain/plasma ratio(Bu/Pu) as measured in vivo pharmacokinetic studies in rodents. Othermethods for assessing brain penetration are known to persons of ordinaryskill in the art. See, for example, Liu, X. et al., J. Pharmacol. Exp.Therap., 325:349-56, 2008.

In view of the many possible embodiments to which the principles of thepresent disclosure may be applied, it should be recognized that theillustrated embodiments are only preferred examples and should not betaken as limiting. Rather, the scope of the present disclosure isdefined by the following claims. We therefore claim as our invention allthat comes within the scope and spirit of these claims.

We claim:
 1. A compound, having a Formula I

wherein X is C or N; Y is O; the ring system denoted by

is a bicyclic heteroaryl optionally substituted on ring A, ring B, orboth by one or more R⁴ groups; L is a divalent moiety selected fromR^(a), a heteroatom; —CH₂—, —CH₂CH₂—, or C₃₋₆ cycloalkyl; Z isC₁₋₁₀aliphatic, heteroaryl or aromatic; each R¹ independently is 8- to12-membered spiroheterocyclyl or a -linker-R⁶ group, wherein the linkeris C₂₋₁₀alkyne, and R⁶ is heterocyclyl, R^(b), —C(R^(f))₃, or—C(R^(f))═C(R^(f))₂; R² is R^(a); each R⁴ independently is oxo,C₃₋₆heterocyclyl or R^(e); R^(a) is independently for each occurrence Hor D, except for embodiments where L is R^(a), C₁₋₁₀aliphatic,C₁₋₁₀haloaliphatic, C₅₋₁₀aromatic, C₃₋₆heterocyclic, orC₃₋₁₀spiroheterocyclic; R^(b) is independently for each occurrence —OH,—SH, —OR^(c), —SR^(c), —NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c),—C(O)NR^(d)R^(d), —OC(O)NR^(d)R^(d), —OC(O)C₁₋₁₀alkyl substituted withone or two NR^(d)R^(d), carboxyl, or a combination thereof, andoptionally further substituted with an aromatic moiety, —SH, —O-acyl, or—C(O)NH₂; R^(c) is independently for each occurrence C₁₋₁₀alkyl, whichcan be substituted with 1, 2 or 3 R^(e), C₂₋₁₀alkenyl, which can besubstituted with 1, 2 or 3 R^(e), C₂₋₁₀alkynyl, which can be substitutedwith 1, 2 or 3 R^(e), C₃₋₆cycloalkyl, which can be substituted with 1, 2or 3 R^(e), or C₅₋₁₀aromatic, which can be substituted with 1, 2 or 3R^(e); R^(d) is independently for each occurrence H; C₁₋₆ alkyl, whichcan be substituted with 1, 2 or 3 R^(e) or a C₃₋₉heterocyclyl;C₃₋₆cycloalkyl, which can be substituted with 1, 2 or 3 R^(e);C₃₋₆heterocyclic, which can be substituted with 1, 2 or 3 R^(e);C₅₋₁₀aryl, which can be substituted with 1, 2 or 3 R^(b);C₅₋₁₀heteroaryl, which can be substituted with 1, 2 or 3 R^(e); or twoR^(d) groups together with the nitrogen bound thereto provide a C₃₋₉heterocyclic, which can be substituted with one or more R^(e)), or aC₅₋₁₀heteroaryl, which can be substituted with one or more R^(e); R^(e)is independently for each occurrence halogen, C₁₋₆alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, C₅₋₁₀heteroaryl, or—OR^(a); and R^(f) is independently for each occurrence-alkyl-phosphate, R^(a), R^(b), or R^(e), or two R^(f) groups togetherwith the carbon atom bound thereto provide a C₂₋₆ alkenyl group, aC₃₋₆cycloalkyl group, which can be substituted with one or more R^(e),or a C₃₋₁₀heterocyclic, which can be substituted with one or more R^(e)or acyl; m is 1, 2, 3, or 4; and n is 0, 1 or
 2. 2. The compound ofclaim 1 according to the formula


3. The compound of claim 1 according to the formula


4. The compound of claim 1 according to the formula


5. The compound of claim 1, wherein ring B is 5-membered or 6-memberedheteroaryl wherein the heteroaryl has one or two ring nitrogen atoms andthe remainder of the ring atoms are carbon.
 6. The compound of claim 1,wherein the ring system denoted by

has the formula

wherein p is 0 or 1; and ring A, ring B, or both optionally aresubstituted by one or more R⁴.
 7. The compound of claim 1, wherein thering system denoted by

has the formula

wherein p is 0 or 1; and ring B is optionally substituted by one or moreR⁴.
 8. The compound of claim 1, wherein the ring system denoted by

has the formula

wherein p is 0 or
 1. 9. The compound of claim 1, wherein the ring systemdenoted by

has the formula


10. The compound of claim 1, wherein the ring system denoted by

has the formula


11. The compound of claim 1, according to the formula

wherein ring B is 5-membered or 6-membered heteroaryl wherein theheteroaryl has one or two ring nitrogen atoms and the remainder of thering atoms are carbon; L is a heteroatom or R^(a), provided that R^(a)is not H or D; Z is C₁₋₁₀aliphatic or aromatic; each R¹ independently is8- to 12-membered spiroheterocyclyl or a -linker-R⁶ group, wherein thelinker is C₂-C₁₀alkyne, and R⁶ is heterocyclyl, R^(b), —C(R^(f))₃, or—C(R^(f))═C(R^(f))₂; R² is R^(a); R³ is C₁₋₃ aliphatic optionallysubstituted with one or more R⁴, wherein together with the —N—C(O)moiety to which it is attached and two ring atoms from ring B forms a 5-or 6-membered heterocyclyl that is fused to ring B; each R⁴independently is R^(e); R^(a) is independently for each occurrence H orD, except for embodiments where L is R^(a), C₁₋₁₀aliphatic,C₁₋₁₀haloaliphatic, C₅₋₁₀aromatic, C₃₋₆heterocyclic, orC₃₋₁₀spiroheterocyclic; R^(b) is independently for each occurrence —OH,—SH, —OR^(c), —SR^(c), —NR^(d)R^(d), —Si(R^(a))₃, —C(O)OH, —C(O)OR^(c),—C(O)NR^(d)R^(d), —OC(O)NR^(d)R^(d), —OC(O)C₁₋₁₀alkyl substituted withone or two NR^(d)R^(d), carboxyl, or a combination thereof, andoptionally further substituted with an aromatic moiety, —SH, —O-acyl, or—C(O)NH₂; R^(c) is independently for each occurrence C₁₋₁₀alkyl, whichcan be substituted with 1, 2 or 3 R^(e), C₂₋₁₀alkenyl, which can besubstituted with 1, 2 or 3 R^(e), C₂₋₁₀alkynyl, which can be substitutedwith 1, 2 or 3 R^(e), C₃₋₆cycloalkyl, which can be substituted with 1, 2or 3 R^(e), or C₅₋₁₀aromatic, which can be substituted with 1, 2 or 3R^(e); R^(d) is independently for each occurrence H; C₁₋₆ alkyl, whichcan be substituted with 1, 2 or 3 R^(e) or a C₃₋₉heterocyclyl;C₃₋₆cycloalkyl, which can be substituted with 1, 2 or 3 R^(e);C₃₋₆heterocyclic, which can be substituted with 1, 2 or 3 R^(e);C₅₋₁₀aryl, which can be substituted with 1, 2 or 3 R^(b);C₅₋₁₀heteroaryl, which can be substituted with 1, 2 or 3 R^(e); or twoR^(d) groups together with the nitrogen bound thereto provide aC₃₋₉heterocyclic, which can be substituted with one or more R^(e)), or aC₅₋₁₀heteroaryl, which can be substituted with one or more R^(e); R^(e)is independently for each occurrence halogen, C₁₋₆alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₅₋₁₀heteroaryl, or—OR^(a); and R^(f) is independently for each occurrence-alkyl-phosphate, R^(a), R^(b), or R^(e), or two R^(f) groups togetherwith the carbon atom bound thereto provide a C₂₋₆alkenyl group, aC₃₋₆cycloalkyl group, which can be substituted with one or more R^(e),or a C₃₋₁₀heterocyclic, which can be substituted with one or more R^(e)or acyl; m is 1, 2, 3, or 4; and n is 0, 1 or
 2. 12. The compoundaccording to claim 1, wherein ring B is pyrazolyl or pyridinyl.
 13. Thecompound according to claim 1, wherein: ring B is pyridinyl orpyrazolyl; L is a heteroatom or C₁₋₁₀aliphatic; Z is C₁₋₁₀aliphatic oraromatic; R² is H or C₁₋₁₀aliphatic; each R⁴ independently is halogen orC₁₋₁₀aliphatic; m is 1, 2, 3, or 4; and n is 0, 1 or
 2. 14. The compoundaccording to claim 11, wherein the compound has a formula


15. The compound according to claim 11, wherein the compound has aformula:


16. The compound according to claim 11, wherein the compound has aformula:


17. The compound according to claim 11, wherein the compound has aformula:


18. The compound according to claim 11, wherein the compound has aformula:


19. The compound according to claim 1, wherein the compound has aformula


20. The compound according to claim 19, wherein the compound has aformula


21. The compound according to claim 20, wherein R² is H or C₁₋₆alkyl.22. The compound according to claim 21, wherein R² is methyl.
 23. Thecompound according to claim 1, wherein each R⁴ independently is halogenor C₁₋₆alkyl.
 24. The compound according to claim 23, wherein each R⁴independently is chloro, fluoro or methyl.
 25. The compound accordingclaim 23, wherein n is 0 or
 1. 26. The compound according to claim 1,wherein L is C₁₋₆alkyl.
 27. The compound according to claim 1, wherein Lis —CH₂—.
 28. The compound according to claim 1, wherein Z is aryl orC₃₋₆cycloalkyl.
 29. The compound according to claim 20, wherein: Z is

each R⁵ independently is R^(e); and q is 0, 1, 2, 3, 4, or
 5. 30. Thecompound according to claim 29, wherein each R⁵ independently is halogenor C₁₋₆ alkyl.
 31. The compound according to claim 30, wherein each R⁵independently is methyl or fluoro.
 32. The compound according to claim30, wherein n is 0, 1 or
 2. 33. The compound according to claim 28,wherein Z is cyclobutyl or cyclopentyl.
 34. The compound according toclaim 1, wherein Z is C₁₋₆alkyl.
 35. The compound according to claim 34,wherein Z is methyl.
 36. The compound according to claim 1, wherein Z isheteroaryl.
 37. The compound according to claim 36, wherein Z ispyridinyl.
 38. The compound according to claim 1, wherein the L-Z moietyis_phenoxy, 4-fluorophenoxy, 3-fluorophenoxy, 2-fluorophenoxy,2,4-difluorophenoxy, 2,6-difluorophenoxy, 4-fluorobenzyl,2,6-dimethylphenoxy, cyclobutyloxy, cyclopentyloxy, methoxy,4-methylphenoxy, benzyl, (6-methylpyridin-2-yl)methyl or(6-fluoropyridin-2-yl)methyl.
 39. The compound according to claim 1,wherein each R¹ independently is 8- to 12-membered sprioheterocyclylsubstituted with one or two substituents selected from —OH, halogen,carboxyl, carboxyl ester, heterocyclyl, amino, alkoxy, phosphate,cycloalkyl, alkenyl, —OC(O)NH(C₁₋₄alkyl)-amino, —OC(O)R⁸, or—OC(O)(CHR⁹)₂CO₂H; wherein the —OC(O)-R⁸ is derived from an amino acidwhere the —OC(O)-moiety of —OC(O)-R⁸ corresponds to an acid moiety onthe amino acid and R⁸ comprises —N(R¹⁰)₂ or a nitrogen-containingnonaromatic heterocyclyl, wherein R¹⁰ is H or carboxyl ester; and eachR⁹ independently is H or —O-acyl.
 40. The compound according to claim39, wherein the amino acid is a naturally occurring amino acid.
 41. Thecompound of claim 40 wherein the naturally occurring amino acid isselected from glycine, valine, alanine, leucine, isoleucine, methionine,phenylalanine, tryptophan, tyrosine, serine, threonine, asparagine,glutamine, arginine, histidine, lysine, aspartic acid, glutamic acid,cysteine, or proline.
 42. The compound according to claim 1, wherein atleast one R¹ is 8-to 12-membered spiroheterocyclyl.
 43. The compoundaccording to claim 1, wherein at least one R¹ is a C₂₋₁₀alkyne.
 44. Thecompound according to claim 43, wherein the C₂₋₁₀alkyne has one or twosubstituents and one substituent is oxetanyl, azetidinyl, pyridinyl,pyrrolidinyl, piperidinyl, tetrahydropyranyl, or phosphate.
 45. Thecompound according to claim 43, wherein at least one R¹ is a C₂₋₁₀alkynesubstituted with one or two substituents and one substituent is—OC(O)-R⁸, wherein the —OC(O)-R⁸ is derived from an amino acid where the—OC(O)—moiety of —OC(O)-R⁸ corresponds to an acid moiety on the aminoacid and R⁸ comprises —N(R¹⁰)₂ or a nitrogen-containing nonaromaticheterocyclyl, wherein R¹⁰ is H or carboxyl ester.
 46. The compoundaccording to claim 1, wherein at least one R¹ is selected from any ofthe following:


47. The compound according to claim 1, wherein the compound is selectedfrom I-1:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-2:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-3:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((1-hydroxycyclopentyl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-4:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-4-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-5:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-3-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-6:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-7:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-(tert-butoxy)prop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-8:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-9:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-10:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-11: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo [3,4-c]pyrazol-5(4H)-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-12:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-13: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo [3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-14: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo [3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-15:(S)-6-((3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)ethynyl)picolinonitrile;I-16: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo [3,4-c]pyrazol-5(4H)-yl)-5-methyl-7-(7-oxa-2-azaspiro[30.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one; I-17:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-18:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-19:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-′7-(3-hydroxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-20: (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyrrolidin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-21:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one; I-22:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;and I-23:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one.
 48. A compound, selected from: I-1:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-2:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-3:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((1-hydroxycyclopentyl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-4:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-4-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-5:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-3-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-6:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-7:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-(tert-butoxy)prop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-8:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-9:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-10:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(3-methoxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-11: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo [3,4-c]pyrazol-5(4H)-yl)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-12:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-(4-hydroxy-3,3-dimethylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-13: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-(6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-14: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-8-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-15:(S)-6-((3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)ethynyl)picolinonitrile;I-16: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-17:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-18:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyridin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-19:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxyprop-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-20: (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(pyrrolidin-2-ylethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-21:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-((6-methylpyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;I-22:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one;and I-23:(S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one.49. A compound, having a formula


50. A pharmaceutical composition, comprising the compound according toclaim 1, and a pharmaceutically acceptable excipient, a therapeuticagent, or combinations thereof.
 51. A method comprising administeringthe compound of claim 1 to a subject having a disease, wherein thedisease is myelodysplastic syndrome.
 52. A method comprisingadministering the compound of claim 1 to a subject having a disease,wherein the disease is atopic dermatitis, rheumatoid arthritis, orankylosing spondylitis.
 53. A method comprising administering thecompound of claim 1 to a subject having a disease, wherein the diseaseis an inflammatory or immune-regulatory disorder.
 54. A methodcomprising administering the compound of claim 1 to a subject having adisease, wherein the disease is an aging disorder.
 55. A methodcomprising administering the compound of claim 1 to a subject having adisease, wherein the disease is selected from amyotrophic lateralsclerosis (ALS), an autoimmune syndrome, rheumatoid arthritis, type Idiabetes mellitus, inflammatory bowel diseases, including Crohn'sdisease and ulcerative colitis, biliary cirrhosis, multiple sclerosis,Wegener's granulomatosis, ichthyosis, asthma, pollen allergies,reversible obstructive airway disease, bronchial asthma, allergicasthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic orinveterate asthma, late asthma and airway hyper-responsiveness, allergicrhinitis, spondyloarthritis, ankylosing spondylitis, autoimmunehepatitis, autoimmune hepatobiliary diseases, cerebrovascular accident,allergic diseases, chronic obstructive pulmonary disease, pulmonaryemphysema, Friedreich's ataxia, Lewy body disease, diabetic neuropathy,polyglutamine (polyQ) diseases, Fahr disease, Menke's disease, Wilson'sdisease, prion disorder, destructive bone disorders such as boneresorption disease, multiple myeloma-related bone disorder; benigntumor, proliferative disorders, inflammatory and hyperproliferative skindisorders, an epidermal hyperproliferation, psoriasis, atopicdermatitis, contact dermatitis, eczematous dermatitis, seborrhoeicdermatitis, pustular psoriasis, bullous dermatitis, dermatitis erythemamultiforme, linear IgA bullous dermatitis, cement dermatitis,gingivitis, periodontitis, lesions of gingiva, alveolar bone, substantiaossea dentis, sepsis, pancreatitis, lichen planus, pemphigus, bullouspemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitis,erythema, cutaneous eosinophilia, adiposis, eosinophilic fascitis, acne,alopecia areata, male pattern alopecia, alopecia senilis,keratoconjunctivitis, vernal conjunctivitis, corneal alkali burn,Behcet's disease, uveitis associated with Behcet's disease, keratitis,herpetic keratitis, conical cornea, dystrophia epithelialis corneae,corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis,Vogt-Koyanagi-Harada syndrome, hematological disorders, hematologicalmalignancies, lymphomas, Hodgkins lymphoma, non-Hodgkins lymphoma,mammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, ABC diffuse large B-celllymphoma (DLBCL), Waldenström's macroglobulinemia, primary cutaneousT-cell lymphoma, smoldering or indolent multiple myeloma, leukemia,acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL),chronic lymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS),myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginalzone lymphoma, multiple myeloma, plasmacytoma, intravascular largeB-cell lymphoma, IL-1 driven disorders, MyD88 driven disorders, drugresistant malignancies, such as JAK inhibitor-resistant malignancies andibrutinib resistant malignancies, for example ibrutinib resistanthematological malignancies, ibrutinib resistant CLL and ibrutinibresistant Waldenström's macroglobulinemia, acute myelogenous leukemia,chronic myelogenous leukemia; angiogenic disorders such as angiogenicdisorders including solid tumors, ocular neovascularization,hemangiomas, such as infantile hemangiomas; sepsis, septic shock,shigellosis; migraine, bronchitis, gastric ulcers, necrotizingenterocolitis, intestinal lesions associated with thermal burns, celiacdiseases, proctitis, eosinophilic gastroenteritis, mastocytosis,interleukin-1 converting enzyme-associated associated fever syndrome,tumor necrosis factor receptor-associated periodic syndrome,NEMO-deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chainassembly complex deficiency syndrome, a lysosomal storage disease,Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis,aspartylglucosaminuria, cholesteryl ester storage disease, chronichexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease,Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis,mucolipidosis, infantile free sialic acid storage disease, juvenilehexosaminidase A deficiency, Krabbe disease, lysosomal acid lipasedeficiency, metachromatic leukodystrophy, mucopolysaccharidosesdisorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronalceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease,Schindler disease, sialic acid storage disease, Tay-Sachs disease,Wolman disease, Huntington's disease, Parkinson's disease,neurodegenerative diseases, Huntington's disease, Parkinson's disease,metastatic melanoma, neurodegeneration associated with HIV infection andCMV retinitis, such as associated neurocognitive disorders or dementia,fibrotic conditions such as, nonalcoholic steatohepatitis and cardiacconditions such as, ischemia reperfusion; allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, erythematosis, chronic thyroiditis, Graves' disease,autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graftversus host disease, inflammatory reaction induced by endotoxin,tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter'ssyndrome, rubella arthritis, acute synovitis, pancreatic β-cell disease;diseases characterized by massive neutrophil infiltration; rheumatoidspondylitis, gouty arthritis, psoriatic arthritis, and other arthriticconditions, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoidosis, fibroid lung, idiopathic interstitialpneumonia, allograft rejection, bone marrow rejection, fever andmyalgias due to infection, keloid formation, scar tissue formation,pyresis, influenza, chronic myelogenous leukemia; angiogenic disordersincluding solid tumors; viral diseases including acute hepatitisinfection (including hepatitis A, hepatitis B and hepatitis C), AIDS,ARC or malignancy, herpes; stroke, myocardial infarction,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardial ischemia, ischemia in stroke heart attacks, organhypoxia, vascular hyperplasia, cardiac and renal reperfusion injury,ischemia-reperfusion injury of organs which occurs upon preservation,transplantation or ischemic disease, cardiac hypertrophy,thrombin-induced platelet aggregation, endotoxemia and/or toxic shocksyndrome, conditions associated with prostaglandin endoperoxidasesyndase-2, pemphigus vulgaris, autoimmune/multiple myositis,dermatomyositis, leukoderma vulgaris, photoallergic sensitivity,ischemia reperfusion injury, cardiac ischemia reperfusion injury arisingfrom myocardial infarction, multiple system atrophy, Parkinson-plussyndromes, frontotemporal dementia, intracranial hemorrhage, cerebralhemorrhage, progressive muscular atrophy, pseudobulbar palsy,progressive bulbar palsy, spinal muscular atrophy, inherited muscularatrophy, peripheral neuropathies, progressive supranuclear palsy,corticobasal degeneration, demyelinating diseases, systemic onsetjuvenile idiopathic arthritis (SoJIA) or Still's disease, systemic lupuserythematosus (SLE), Sjögren's syndrome, anti-phospholipid syndrome(APS), primary sclerosing cholangitis (PSC), renal transplant, surgery,acute kidney injury (AKI), systemic inflammatory response syndrome(SIRS), cytokine release syndrome (CRS), acute respiratory distresssyndrome (ARDS), ARDS resulting from COVID-19, postinfectious autoimmunediseases, rheumatic fever, post-infectious glomerulonephritis, systemicsclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonarydisease (COPD), NEMO-deficiency syndrome (F-kappa-B essential modulatorgene (also known as IKK gamma or IKKG) deficiency syndrome), solid organmalignancies, lysosomal storage diseases, glaucoma, retinal degenerativedisease, retinal ischemia/reperfusion injury, renal ischemia reperfusioninjury, cataracta, siderosis, retinitis pigmentosa, retinaldegeneration, retinal detachment, senile macular degeneration, vitrealscarring, anthrax lethal toxin induced septic shock, cell death inducedby LPS, infectious encephalopathy, encephalitis, allergicencephalomyelitis, autoimmune uveoretinitis, giant cell arteritis,regional enteritis, granulomatous enteritis, distal ileitis, regionalileitis, terminal ileitis, insulin-dependent diabetes mellitus,scleroderma, systemic scleroderma, macular edema, diabetic retinopathy,central areolar choroidal dystrophy, BEST disease, adult vitelliformdisease, pattern dystrophy, myopic degeneration, central serousretinopathy, Stargardt's disease, Cone-Rod dystrophy, North Carolinadystrophy, infectious retinitis, inflammatory retinitis, uveitis,posterior uveitis, toxic retinitis and light-induced toxicity, macularedema, central areolar choroidal dystrophy, BEST disease, adultvitelliform disease, pattern dystrophy, optic nerve injury, opticneuritis, optic neuropathies, central retinal artery occlusion, ischemicoptic neuropathy (e.g., arteritic or non-arteritic anterior ischemicneuropathy and posterior ischemic optic neuropathy), compressive opticneuropathy, infiltrative optic neuropathy, traumatic optic neuropathy,mitochondrial optic neuropathy (e.g., Leber's optic neuropathy),nutritional optic neuropathy, toxic optic neuropathy and hereditaryoptic neuropathy, Dominant Optic Atrophy, Behr's syndrome,Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditaryspastic paresis, subarachnoid hemorrhage, perinatal brain injury,subclinical brain injury, spinal cord injury, anoxic-ischemic braininjury, cerebral ischemia, focal cerebral ischemia, global cerebralischemia, and hypoxic hypoxia, peritoneal damage caused by peritonealdialysis fluid (PDF) and PD-related side effects, glomerular diseases,tubulointerstitial diseases, interstitial nephritis, obstruction,polycystic kidney disease), focal glomerulosclerosis, immune complexnephropathy, diabetic nephropathy, Goodpasture's syndrome,hepatocellular cancer, pancreatic cancer, urological cancer, bladdercancer, colorectal cancer, colon cancer, breast cancer, prostate cancer,prostate hyperplasia, renal cancer, kidney carcinoma, liver carcinoma,adrenal gland carcinoma, thyroid cancer, gall bladder cancer, peritonealcancer, ovarian cancer, cervical cancer, gastric cancer, endometrialcancer, esophageal cancer, stomach cancer, head and neck cancer,neuroendocrine cancer, CNS cancer, brain tumors (e.g., carcinoma of thebrain, glioma, anaplastic oligodendroglioma, adult glioblastomamultiforme, and adult anaplastic astrocytoma), bone cancer, soft tissuesarcoma, retinoblastomas, neuroblastomas, peritoneal effusions,malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblasticneoplasms, epithelial neoplasia, stomach carcinoma, carcinoma of theovaries, rectum carcinoma, prostate carcinoma, carcinoma of thepancreas, lung carcinoma, carcinoma of the vagina, carcinoma of thecervix, carcinoma of the testis, carcinoma of the genitourinary tract,carcinoma of the esophagus, carcinoma of the larynx, carcinoma of theskin, carcinoma of the bone, carcinoma of the thyroid, sarcoma,glioblastomas, neuroblastomas, gastrointestinal cancer, adenoma,adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cellcarcinoma, non-small-cell lung carcinoma, lymphomas, colon carcinoma,colorectal adenoma, hemangiopericytomas, myxoid carcinoma, round cellcarcinoma, squamous cell carcinomas, esophageal squamous cellcarcinomas, oral carcinomas, vulval cancer, cancers of the adrenalcortex, ACTH producing tumors, and leukemia, respiratory infectiousviruses, such as influenza virus, rhinovirus, corona virus,parainfluenza virus, RS virus, adeno virus, reo virus and the like),herpes zoster caused by herpes virus, diarrhea caused by rotavirus,viral hepatitis, AIDS, bacterial infectious diseases, such as Bacilluscereus, Vibrio parahaemolyticus, Enterohemorrhagic Escherichia coli,Staphylococcus aureus, MRS A, Salmonella, Botulinus, Candida, Paget'sdisease, achondroplasia, osteochodrytis, hyperparathyroidism,osteogenesis imperfecta, partial liver resection, acute liver necrosis,necrosis caused by toxin, necrosis caused by viral hepatitis, necrosiscaused by shock, necrosis caused by anoxia, B-virus hepatitis,non-A/non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholiccirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis(NASH), acetaminophen toxicity, hepatotoxicity, hepatic failure,fulminant hepatic failure, late-onset hepatic failure,“acute-on-chronic” liver failure, chronic kidney diseases, kidneydamage/injury, kidney damage/injury caused by nephritis, kidneydamage/injury caused by renal transplant, kidney damage/injury caused bysurgery, kidney damage/injury caused by administration of nephrotoxicdrugs, augmentation of chemotherapeutic effect, cytomegalovirusinfection, HCMV infection, AIDS, cancer, senile dementia, trauma,chronic bacterial infection, diseases caused by environmental pollution,aging, hypobaropathy, disease caused by histamine or leukotriene-C4release, muscular dystrophy, pyoderma and Sezary's syndrome, Addison'sdisease, pseudomembranous colitis, colitis caused by drug or radiation,ischemic acute renal insufficiency, chronic renal insufficiency,toxinosis caused by lung-oxygen or drugs, congenital hypophosphatasia,fibromatous lesions, fibrous displasia, bone turnover, osteolytic bonedisease, treating post-traumatic bone surgery, treating post-prostheticjoint surgery, treating post-plastic bone surgery, treating post-dentalsurgery, bone chemotherapy treatment or bone radiotherapy treatment,bone cancer, fragile plaque, disorder, occlusive disorder, stenosis,coronary artery disorders, peripheral arterial disorders, arterialocclusion, aneurysm formation, post-traumatic aneurysm formation,restenosis, post-operative graft occlusion, Guillain-Barre syndrome,Meniere's disease, polyneuritis, multiple neuritis, mononeuritis,radiculopathy, hyperthyroidism, Basedow's disease, autoimmune idiopathicthrombocytopenic purpura (autoimmune ITP), membranous nephritis,autoimmune thyroiditis, Hashimoito's thyroiditis, myasthenia gravis,cold and warm agglutinin diseases, Evan's syndrome, hemolytic uremicsyndrome/thrombotic thrombocytopenic purpura (HUS/TTP), autoimmunehemolytic anemia, agranulocytosis, pernicious anemia, megaloblasticanemia, anerythroplasia, or a combination thereof.